Formulation and method for treating neoplasms by inhalation

ABSTRACT

A formulation, method, and apparatus for treating neoplasms such as cancer by administering a pharmaceutically effective amount of highly toxic composition by inhalation, wherein the composition is a non-encapsulated antineoplastic drug.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/033,789 filed on Dec. 30, 1996.

FIELD OF THE INVENTION

[0002] The invention deals with formulations and methods useful fortreating neoplasms, particularly neoplasms of the respiratory tract(e.g. lung cancer and cancers of the head and neck), by pulmonaryadministration of highly toxic or vesicating anticancer drugs.Additionally, several new formulations and methods for treatingneoplasms using antineoplastic drugs that are nonvesicants are alsodisclosed.

BACKGROUND OF THE INVENTION

[0003] Cancer is one of the leading causes of death worldwide. Lungcancer in particular, is among the top 3 most prevalent cancers and hasa very poor survival rate (about 13% five-year survival rate). Despitethe availability of many cancer drugs it has been difficult and, in thecase of some cancer types, almost impossible to improve cure rates orsurvival. There are many reasons for this lack of success but one reasonis the inability to deliver adequate amounts of the drugs to the tumorwithout causing debilitating and life-threatening toxicities in thepatient. Indeed, most chemotherapeutic drugs used to treat cancer arehighly toxic to both normal and tumor tissues.

[0004] It is customary in the treatment of cancer to administer thedrugs by the intravenous route, which exposes the entire body to thedrug. Doses are selected that destroy tumor cells, but these doses alsodestroy normal cells. As a result, the patient usually experiencessevere toxic side effects. For example, severe myelosuppression mayresult which compromises the ability of the patient to resist infectionand allows spread of the tumor. There are other life-threatening effectssuch as hepatotoxicity, renal toxicity, pulmonary toxicity,cardiotoxicity, neurotoxicity, and gastrointestinal toxicity caused byanticancer drugs. The anticancer drugs also cause other effects such asalopecia, stomatitis, and cystitis that may not be life threatening, butare serious enough to affect a patient's quality of life. Moreover, itis important to note that these toxicities are not associated to thesame extent with all anticancer drugs but are all due to systemicdelivery of the drug.

[0005] Although myelosuppression is commonly associated with mostanticancer drugs, because of differences in the mechanisms by which thevarious anticancer drugs act or in the ways they are distributed in thebody, metabolized and excreted from the body, each drug presents asomewhat different toxicity profile, both quantitatively andqualitatively. For example, anthracyclines such as doxorubicin,epirubicin and idarubicin are known to cause severe cardiotoxicity.Doxorubicin, additionally, is known to cause severe progressive necrosisof tissues when extravasated. Cisplatin therapy is known to cause renaltoxicity; vincristine causes neurotoxicity, bleomycin and mitomycincause pulmonary toxicity, cyclophosphamide causes cystitis; and5-fluorouracil causes cerebral disjunction (see Cancer Chemotherapy:Principles and Practice, B. A. Shabner and J. M. Collings, eds. J. B.Lippincott Co., Philadelphia, 1990).

[0006] The differences in mechanisms of action and pharmacokineticproperties determine, in part, the efficacy of the various anticancerdrugs against different tumor types, which exhibit various biologicalbehaviors.

[0007] Some attempts have been made to deliver anticancer drugs directlyto the tumor or to the region of the tumor to minimize exposure ofnormal tissues to the drug. This regional therapy, for example has beenused to treat liver cancer by delivering drugs directly into the hepaticartery so that the full dose goes to the liver while reducing the amountthat goes to the rest of the body. For the treatment of urinary bladdercancer, anticancer drugs are instilled directly into the bladder throughthe urethra, allowed to remain in contact with the tumor for a period oftime and then voided. Other examples of regional therapy include thedelivery of anticancer drugs into the peritoneal cavity to treat cancerthat has developed in or metastasized to this location. Other methods oftargeting anticancer drugs involve the attachment of the drugs toantibodies that seek out and deliver the drug directly to the cancercells.

[0008] In 1968 Shevchenko, I. T., (Neoplasma 15, 4, 1968) pp.419-426reported on the treatment of advanced bronchial cancer using acombination of inhalation of chemotherapeutic agents, radiotherapy, andoxygen inhalation. The reported chemotherapeutic agents were benzotaph,thiophosphamid, cyclophosphan and endoxan that were applied as anaerosol by means of an inhaler. For 58 treated patients the combinationof three treatments showed tumor disappearance in 8 cases while in 6 thesize of the tumor diminished considerably. The study did not include acontrol group.

[0009] In 1970, Sugawa, I. (Ochanoizu Med. J.; Vol. 18; No.3; (1970),pp.103-114, reported on tests using mitomycin-C in the treatment ofmetastatic lung cancer. One of four patients treated reportedly showedsome improvement. Inhalation of mitomycin-C also appeared to reducetumor growth in IV-inoculated tumors in rabbits; results appeared to bemore inconclusive in rats. Tests were conducted to determine the toxiceffects to the respiratory tract following intrabronchial infusions ofseveral drugs. The drugs were given to healthy animals and included:thiotepa (rats), Toyomycin (chromomycin A3) (rats,), endoxan(cyclophosphamide) (rats and rabbits), 5-fluorourcil (rats and rabbits),mitomycin-C (rats, rabbits, and dogs). The results of these tests showedthat: 5-FU and cyclophosphamide resulted in only mild inflammation;thiotepa produced bronchial obstruction; chromomycin A3 and mitomycin-Cproduced the most severe results. Toxic effects of mitomycin-C andchromomycin A3 were studied in rabbits and dogs.

[0010] In 1983, Tatsumura et al (Jap. J. Cancer Cln., Vol. 29, pp.765-770) reported that the anticancer drug, fluorouracil (5-FU, MW=130)was effective for the treatment of lung cancer in a small group of humanpatients when administered directly to the lung by aerosolization. Theyreferred to this as nebulization chemotherapy. It was also noted byTatsamura et al (1993) (Br. J. Cancer, Vol. 68(6): pp.1146-1149) thatthe 5-FU did not cause toxicity to the lung. This finding was nottotally unexpected because 5-FU has a very low molecular weight and doesnot bind tightly to proteins. Therefore, it passes through the lungrapidly lessening the opportunity to cause local toxicity. Moreover 5-FUis considered to be one of the least toxic anticancer drugs when applieddirectly to tissue. Indeed, 5-FU is used as a topical drug for thetreatment of actinic keratosis for which it is applied liberally, twicedaily, to lesions on the face. This therapy may continue for up to fourweeks. Also, because 5-FU is poorly absorbed from the gastrointestinaltract, there is little concern about the amount of drug that may beinadvertently swallowed and gain access to the blood stream from thegut. It is well known that a large percentage of aerosolized drugintended for the lung is swallowed.

[0011] Another report includes the use of β-cytosine arabinoside (Ara-C,cytarabine, MW=243) administered via intratracheal delivery to therespiratory system of rats. Liposome encapsulated and free Ara-C wereinstilled intratracheally to the rats as a bolus. The encapsulated Ara-Cpersisted for a long time in the lung while the free Ara-C which is nothighly protein bound was rapidly cleared from the lung. The free Ara-Crapidly diffused across the lung mucosa and entered the systemiccirculation. The paper suggests that liposome encapsulation of drugs maybe a way to produce local pharmacologic effect within the lung withoutproducing adverse side effects in other tissues. However, bolusadministration results in multifocal concentrated pockets of drug. Seethe articles by H. N. MacCullough et al, JNCI, Vol. 63, No. 3,September, pp.727-731 (1979) and R.L. Juliano et al, J. Ph. & Exp.Ther., Vol. 214, No.2, pp.381-387 (1980).

[0012] An additional report includes the use of cisplatin (MW=300) forinhalation chemotherapy in mice that had been implanted with FM3A cells(murine mammary tumor cells) in the air passages. The cisplatin exposedinhalation group were reported to have statistically smaller lung tumorsizes and survived longer than the untreated control group. See A.Kinoshita, “Investigation of Cisplatin Inhalation Chemotherapy Effectson Mice after Air Passage Implantation of FM3A Cells”, J. Jap. Soc.Cancer Ther. 28(4): pp. 705-715 (1993).

[0013] In U.S. Pat. No. 5,531,219 to Rosenberg, the patent disclosuresuggests the use of doxorubicin, 5-FU, vinblastine sulfate, ormethotrexate in combination with pulmonary infused liquid fluorocarbons.The patient is suggested to be positioned so that the tumor affectedarea is at a gravitational low point so that liquid perfluorocarbonhaving relatively low vapor pressure will pool selectively around thearea with the drug then perfused in the pool of liquid perfluorocarbon.The present invention avoids the problems with positioning of thepatient and further does not require the liquid fluorocarbons used byRosenberg.

[0014] In U.S. Pat. No. 5,439,686 to Desai et al there are disclosedcompositions where a pharmaceutically active agent is enclosed within apolymeric shell for administration to a patient. One of the routes ofadministration listed as possible for the compositions of the inventionis inhalational. Among the listed pharmaceutically active agentspotentially useful in the invention are anticancer agents such aspaclitaxel and doxorubicin. No tests using the inhalational rout ofadministration appear to have been made.

[0015] Although several antineoplastic drugs have been administered toanimals and to humans, for treatment of tumors in the lungs andrespiratory system, the differences in the mechanism of action, andtoxicity profiles among the broad classes of anticancer drugs, and theheretofore known characterizations have made it impossible to predictwhether a particular anticancer drug will be efficacious or toxic basedupon previous inhalation results with a different drug of a differenttype. Further, previous reports used very imprecise means of deliveringdrugs and were not consistent in delivering measured doses of drugs inan evenly distributed manner to the entire respiratory tract. Thepresent invention provides means for predicting and selecting drugsincluding the highly toxic chemotherapeutic compounds, amenable forinhalation therapy of neoplastic disease and methods for actuallydistributing specific measured doses to pre-selected regions of therespiratory tract.

[0016] It has now been demonstrated by the applicants that anticancercytotoxic drugs of multiple classes such as anthracyclines(doxorubicin), antimicrotubule agents such as the vinca alkaloids(vincristine), and taxanes such as paclitaxel can be given directly byinhalation without causing severe toxicity to the lung or other bodyorgans. This finding is surprising, because it is well known among thosewho administer cytotoxins such as doxorubicin to patients, that thisdrug causes severe ulceration of the skin and underlying tissues ifallowed to be delivered outside of a vein. After extravasation the drugcontinues to affect the tissues to such an extent that amputation oflimbs in which the extravasation has occurred has been required. Sosevere is this toxicity that the prescribing information for doxorubicin(and some other similar vesicating drugs) in the Physicians DeskReference contains a “Box Warning” regarding this danger. The presentinvention, therefore, provides an effective way to administerchemotherapeutic agents, including highly toxic agents such asdoxorubicin, while minimizing the major side effects described above.

BRIEF DESCRIPTION OF THE INVENTION

[0017] Broadly, one embodiment of the invention includes a formulationfor treating a patient for a neoplasm by inhalation comprising: a safeand effective amount of a vesicant and a pharmaceutically acceptablecarrier, preferably the vesicant does not exhibit substantial pulmonarytoxicity. In one aspect of the embodiment the vesicant is typically amoderate vesicant such as paclitaxel or carboplatin. A description ofsuch a moderate vesicant would include a non-encapsulated anticancerdrug, wherein when 0.2 ml of the drug is injected intradermally to rats,at the clinical concentration for parenteral use in humans: (a) a lesionresults that is at least 20 mm² in area fourteen days after theintradermal injection; and (b) at least 50% of the tested rats have thissize of lesion. Other aspects of this broad embodiment typically includea vesicant that is a severe vesicant such as doxorubicin, vincristine,and vinorelbine. The neoplasm to be treated is typically a pulmonaryneoplasm, a neoplasm of the head and neck, or other systemic neoplasm.The drug may be in the form of a liquid, a powder, a liquid aerosol, ora powdered aerosol. Typically the patient is a mammal such as a domesticanimal or a human. In other aspects the embodiment includes formulationsof drugs such as etoposide and a carrier such as DMA. Typically thesevere vesicant is an anthracycline such as epirubicin, daunorubicin,methoxymorpholinodoxorubicin, cyanomorpholinyl doxorubicin, doxorubicin,or idarubicin; or a vinca alkaloid such as vincristine, vinorelbine,vinorelbine, vindesine, or vinblastine. In other formulations the drugis typically mechlorethamine, mithramycin, dactinomycin, bisantrene, oramsacrine. Typically the formulation may include a taxane such aspaclitaxel, its derivatives and the like. Typical animal and human dosesare provided in the tables and text below.

[0018] A further broad embodiment of the invention includes aformulation for treating a patient having a neoplasm by inhalationcomprising: a safe and effective amount of a non-encapsulatedantineoplastic drug having a molecular weight above 350, that does notexhibit substantial pulmonary toxicity; and an effective amount of apharmaceutically acceptable carrier. The neoplasm treated with theformulation is typically a pulmonary neoplasm, a neoplasm of the headand neck, or a systemic neoplasm. The drug used in the formulation is inthe form of a liquid, a powder, a liquid aerosol, or a powdered aerosol.Typically the drug has a protein binding affinity of 25% or 50% or more.Further the drug can typically have a higher molecular weights such asabove 400, 450, or 500 daltons. Typical animal and human doses areprovided in the tables and text below.

[0019] In a yet further embodiment of the invention, there is discloseda formulation for treating a patient for a neoplasm by inhalationcomprising: a safe and effective amount of a taxane in an effectiveamount of vehicle comprising polyethyleneglycol (PEG) and an alcohol.Typically the formulation will also contain an acid, where the acidpresent in amount effective to stabilize the taxane. Typically thealcohol is ethanol, and the acid is an inorganic acid such as HCl, or anorganic acid such as citric acid and the like. In some typicalformulations the taxane is paclitaxel and the formulation contains about8% to 40% polyethyleneglycol, about 90% to 60% alcohol, and about 0.01%to 2% acid. Typical animal and human doses are provided in the table andtext below.

[0020] Another embodiment provides for formulations for treating apatient for a neoplasm by inhalation comprising: a safe and effectiveamount of a drug selected from the group consisting of carmustine,dacarbazine, melphalan, mercaptopurine, mitoxantrone, esorubicin,teniposide, aclacinomycin, plicamycin, streptozocin, and menogaril; anda safe and effective amount of a pharmaceutically effective carrier,wherein the drugs do not exhibit substantial pulmonary toxicity.

[0021] A yet further embodiment provides for a formulation for treatinga patient for a neoplasm by inhalation comprising: a safe and effectiveamount of a drug selected from the group consisting of estramustinephosphate, geldanamycin, bryostatin, suramin, carboxyamido-triazoles;onconase, and SU101 and its active metabolite SU20; and a safe andeffective amount of a pharmaceutically effective carrier, wherein thedrugs do not exhibit substantial pulmonary toxicity.

[0022] A still further embodiment provides for a formulation fortreating a patient for a neoplasm by inhalation comprising: a safe andeffective amount of etoposide and an effective amount of a DMA carrier.Typical animal and human doses are provided in the tables and textbelow.

[0023] Another embodiment includes a formulation for treating a patientfor a neoplasm by inhalation comprising: a safe and effective amount ofa microsuspension of 9-aminocamptothecin in an aqueous carrier. Typicalanima and human doses are provided in the tables and text below.

[0024] A further broad embodiment of the invention includes aformulation for treating a patient having a neoplasm comprising:administering to the patient by inhalation, (1) an effective amount of ahighly toxic antineoplastic drug; and (2) an effective amount of achemoprotectant, wherein the chemoprotectant reduces or eliminates toxiceffects in the patient that are a result of administering the highlytoxic antineoplastic drug. Typically the chemoprotectant reduces oreliminates systemic toxicity in the patient, and/or reduces oreliminates respiratory tract toxicity in the patient. Typically theformulation includes a chemoprotectant such as dexrazoxane (ICRF-187),mesna (ORG-2766), ethiofos (WR2721), or a mixture thereof. Thechemoprotectant may be administered before, after, or during theadministration of the antineoplastic drug. The antineoplastic drug usedwith the chemoprotectant may be a nonvesicant, moderate vesicant, or asevere vesicant. Typical among the drugs with which the chemoprotectantis useful are bleomycin, doxorubicin, and mitomycin-C.

[0025] The invention also typically includes a method for treating apatient having a neoplasm comprising: administering to the patient byinhalation, (1) an effective amount of a highly toxic antineoplasticdrug; and (2) an effective amount of a chemoprotectant, wherein thechemoprotectant reduces or eliminates toxic effects in the patient thatare a result of administering the highly toxic antineoplastic drug.Typically the chemoprotectant reduces or eliminates systemic toxicity inthe patient and/or reduces or eliminates respiratory tract toxicity inthe patient. Chemoprotectants can typically be dexrazoxane (ICRF-187),mesna (ORG-2766), ethiofos (WR2721), or a mixture thereof. Thechemoprotectant may be administered before, after, or during theadministration of the antineoplastic drug. Typically the antineoplasticdrug is a nonvesicant, a moderate vesicant, or a severe vesicant.Typically the antineoplastic drug comprises bleomycin, doxorubicin, ormitomycin-C.

[0026] An additional embodiment of the invention includes a method fortreating a patient having a neoplasm comprising: administering a safeand effective amount of a non-encapsulated antineoplastic drug to thepatient by inhalation, the drug selected from the group consisting ofantineoplastic drugs wherein when 0.2 ml of the drug is injectedintradermally to rats, at the clinical concentration for IV use inhumans: (a) at least one lesion per rat results which is greater than 20mm² in area fourteen days after the intradermal injection; and (b) atleast 50% of the tested rats have these lesions. In some typicalembodiments when the drug is doxorubicin or vinblastine sulfate, thedrug is inhaled in the absence of perfluorocarbon. Typical diseasestreated include a neoplasm such as a pulmonary neoplasm, a neoplasm ofthe head and neck, or other systemic neoplasm. The drug may typically beinhaled as inhaled as a liquid aerosol or as a powdered aerosol. Mammalanimals and humans are typical patients treated with the method. Thedrug may typically be selected from the group consisting of doxorubicin,daunorubicin, methoxymorpholino-doxorubicin, epirubicin,cyanomorpholinyl doxorubicin, and idarubicin. When the drug is a vincaalkaloid it is typically selected from the group consisting ofvincristine, vinorelbine, vindesine, and vinblastine. Other useful drugstypically include the alkylating agents mechlorethamine, mithramycin anddactinomycin. Still additional useful drugs typically include bisantreneand amsacrine. The drug can typically be a taxane such as doxitaxel orpaclitaxel.

[0027] Another embodiment of the invention includes a method fortreating a patient having a neoplasm comprising: administering aneffective amount of a highly toxic non-encapsulated antineoplastic drugto a patient by inhalation, wherein the molecular weight of the drug isabove 350, and the drug has no substantial pulmonary toxicity. Typicallythe neoplasm is a pulmonary neoplasm, a neoplasm of the head and neck,or a systemic neoplasm. The drug may be inhaled as a liquid aerosol oras a powdered aerosol. Typically the drug has a protein binding affinityof 25%, 50% or more. In one aspect the drug is typically selected fromthe group comprising doxorubicin, epirubicin, daunorubicin,methoxymorpholinodoxorubicin, cyanomorpholinyl doxorubicin, andidarubicin. If the drug is doxorubicin or vinca alkaloid it may betypically be administered without the presence of a perfluorocarbon.Typically the vinca alkaloid is selected from the group consisting ofvincristine, vinorelbine, vindesine, and vinblastine. Typical alkylatingagent type drugs include mechlorethamine, mithramycin, dactinomycin.Other topoisomerase II inhibitors include bisantrene or amsacrine.

[0028] An additional embodiment includes a method for treating a patientfor a neoplasm by the steps of administering an effective amount of anantineoplastic drug to the patient by inhalation; and administering apharmaceutically effective amount of the same and/or differentantineoplastic drug to the patient parenterally. The patient may betreated with one or more adjunct therapies including radiotherapy,immunotherapy, gene therapy, chemoprotective drug therapy.

[0029] A further embodiment includes a method for treating a patient fora neoplasm including the steps of administering an effective amount ofan antineoplastic drug to the patient by inhalation; and administeringan effective amount of the same and/or different antineoplastic drug tothe patient by isolated organ perfusion. The patient may be treated byone or more adjunct therapies including radiotherapy, immunotherapy,gene therapy, and chemoprotective drug therapy.

[0030] An further embodiment includes a method for treating a patientfor a pulmonary neoplasm by the steps of (1) selecting one or moreantineoplastic drugs efficacious in treating the neoplasm and having aresidence time in the pulmonary mucosa sufficient to be efficacious inthe treatment of the pulmonary neoplasm; and (2) administering thedrug(s) to the patient by inhalation in a non-encapsulated form.Typically when 0.2 ml of at least one of the drugs is injectedintradermally to rats, at the clinical concentration for parenteral usein humans: a lesion results which is greater than 20 mm² in areafourteen days after the intradermal injection; and B. at least 50% ofthe tested rats have these lesions. Typically the molecular weight of atleast one of the selected drugs is above 350.

[0031] A still further embodiment includes a method of use including thesteps of administering one or more non-encapsulated highly toxicanticancer drugs to a mammal by inhalation, wherein at least one of thedrugs comprises a severe vesicant.

[0032] Another embodiment is an apparatus for treating a patient for aneoplasm by inhalation that is a combination of a nebulizer and aformulation for treating a neoplasm, the formulation including (1) anon-encapsulated anticancer drug, and (2) a pharmaceutically acceptablecarrier; wherein when 0.2 ml of the formulation is injectedintradermally to rats, at the clinical concentration for parenteral usein humans: (a) a lesion results which is greater than about 20 mm² inarea fourteen days after the intradermal injection; and (b) at least 50%of the tested rats have these lesions. A further embodiment includes aformulation which when injected results in a lesion which is greaterthan about 10 mm² in area 30 days after the intradermal injection; andat least about 50% of the tested rats have these longer lasting lesions.Typically the formulation includes an anthracycline. Anthracyclines maybe selected from the group consisting of epirubicin, daunorubicin,methoxymorpholinodoxorubicin, cyanomorpholinyl doxorubicin, doxorubicin,and idarubicin. The formulation also typically and contain a vincaalkaloid. Vinca alkaloids may be selected from the group consisting ofvincristine, vinorelbine, vinorelbine, vindesine, and vinblastine.Alternately, the formulation may contain vesicant selected from thegroup consisting of mechlorethamine, mithramycin, and dactinomycin; orbisantrene or amsacrine. Typically the formulation can also contain ataxane which is typically a paclitaxel or doxytaxel.

[0033] Another embodiment of the invention includes an inhalation maskfor administering aerosols to an patient comprising: means for enclosingthe mouth and nose of the patient, having an open end and a closed end,the open end adapted for placing over the mouth and nose of the patient;upper and lower holes in the closed end adapted for insertion of a noseoutlet tube and a mouth inhalation tube; the nose outlet tube attachedto the upper hole, adapted to accept exhaled breath from the nose of thepatient; a one way valve in the nose tube adapted to allow exhalationbut not inhalation; the mouth inhalation tube having an outer and aninner end, partially inserted through the lower hole, the inner endcontinuing to end at the rear of the patients mouth, the inhalation tubeend cut at an angle so that the lower portion extends further into thepatients mouth than the upper portion and adapted to fit the curvatureof the rear of the patients mouth; and a y-adapter attached to the outerend of the mouth inhalation tube. The mask typically will have amoderate vesicant or a severe vesicant present in the inhalation tube.

BRIEF DESCRIPTION OF THE DRAWINGS

[0034]FIG. 1 shows the plasma drug concentration time profile for dog#101 having doxorubicin administered intravenously (IV) (circles) and bythe pulmonary inhalation route (IH) (squares). The vertical Y scale isthe concentration of drug in the circulatory system in ng/ml and thehorizontal X scale is time after treatment in hours.

[0035]FIG. 2 shows the plasma drug concentration time profile for dog#102 having doxorubicin administered intravenously (IV) (circles) and bythe pulmonary inhalation route (IH) (squares). The vertical Y scale isthe concentration of drug in the circulatory system in ng/ml and thehorizontal X scale is time after treatment in hours.

[0036]FIG. 3 shows the plasma drug concentration time profile for dog#103 having doxorubicin administered intravenously (IV) (circles) and bythe pulmonary inhalation route (IH) (squares). The vertical Y scale isthe concentration of drug in the circulatory system in ng/ml and thehorizontal X scale is time after treatment in hours.

[0037]FIG. 4 shows a schematic of the pulmonary delivery apparatusarrangement that was used to administer drug to dogs by inhalation forExample 3.

[0038]FIG. 5 shows a schematic of the pulmonary delivery apparatusarrangement that was used to administer high doses and multiple doses ofdrug to dogs by inhalation for Example 4.

[0039]FIG. 6 shows a schematic drawing of details of a mask useful foradministering drugs by inhalation to a mammal such as a dog.

[0040]FIG. 7 shows a schematic drawing of a portable device foradministration of anticancer drugs according to the invention.

DETAILED DESCRIPTION OF THE INVENTION AND BEST MODE

[0041] The delivery of antineoplastic drugs by inhalation by thepulmonary route is an attractive alternative to the administration ofdrugs by various injectable methods, particularly those drugs that aregiven on a chronic or repeated administration schedule. A cause ofconcern is the toxic nature of the drugs particularly those that arecytotoxic such as the classes represented by alkylating agents, taxanes,vinca alkaloids, platinum complexes, anthracyclines and others that areconsidered particularly toxic especially when administered outside thecirculatory system.

[0042] Broadly, the inventors have discovered that highly toxic,vesicant and previously unknown nonvesicant antineoplastic drugs can beeffectively delivered to a patient in need of treatment for neoplasms orcancers by inhalation. This route is particularly effective fortreatment of neoplasms or cancers of the pulmonary system because thehighly toxic drugs are delivered directly to the site where they areneeded, providing regional doses much higher than can be achieved byconventional IV delivery. As used herein the respiratory tract includesthe oral and nasal-pharyngeal, tracheo-bronchial, and pulmonary regions.The pulmonary region is defined to include the upper and lower bronchi,bronchioles, terminal bronchioles, respiratory bronchioles, and alveoli.

[0043] An important benefit from inhalation therapy for neoplasms of thehead, neck and respiratory tract, is that exposure to the rest of thebody is controlled following administration of high doses of drug andconsequently is spared much of the adverse side effects often associatedwith high doses of systemically administered highly toxic antineoplasticdrugs, yet significantly increased doses are provided at the site of thetumor. These toxic effects include for example: cardiotoxicity,myelosuppression, thrombocytopenia, renal toxicity, and hepatic toxicitythat are often life threatening. The toxic effects are often so severethat it is not uncommon for patients to die from the effects of thesystemically administered drugs rather than from the disease for whichthey are being treated.

[0044] Broadly, vesicants as used herein include chemotherapeutic agentsthat are toxic and typically cause long lasting damage to surroundingtissue if the drug is extravasated. If inadvertently delivered outsideof a vein, a vesicant has the potential to cause pain, cellular damageincluding cellulitis, tissue destruction (necrosis) with the formationof a long lasting sore or ulcer and sloughing of tissues that may beextensive and require skin grafting. In extreme cases extravasation ofvesicants such as doxorubicin has required surgical excision of theaffected area or amputation of the affected limb. Examples ofantineoplastic chemotherapeutic agents that are generally acceptedvesicants include alkylating agents such as mechlorethamine,dactinomycin, mithramycin; topoisomerase II inhibitors such asbisantrene, doxorubicin (adriamycin), daunorubicin, dactinomycin,amsacrine, epirubicin, daunorubicin, and idarubicin; tubulin inhibitorssuch as vincristine, vinblastine, and vindesine; and estramustine. Apartial list of vesicants is found in Table 1.

[0045] In another embodiment, vesicants as more narrowly used hereininclude drugs that produce a lesion in rats, where the average lesionsize is greater than about 20 mm² in area, fourteen days after anintradermal injection of 0.2 ml of the drug, and where 50% or more ofthe animals have this size of lesion. The drug concentration for theintradermal injection is the clinical concentration recommended by themanufacturer for use in humans, the dose recommended in the PhysiciansDesk Reference, 1997 (or a more current version of this reference), oranother drug manual for health specialists. If there is norecommendation by the manufacturer (for example for because the drug isnew) and there is no recommendation in the Physicians Desk Reference orsimilar drug manual for health specialists then other current medicalliterature may be used. If more than one clinical concentration isrecommended, the highest recommended clinical concentration is used.Lesion as used herein means an open sore or ulcer or sloughing off ofskin with exposure of underlying tissue.

[0046] In a yet further embodiment of the invention, 0.2 ml of a highlytoxic anticancer drug (vesicant) at a dose recommended for humans (asdiscussed above) is administered intradermally to rats at aconcentration that causes the above mentioned lesion size for a moreextended period of time. That is, the lesions remain above about 10 mm²up to at least 30 days in at least 50% or more of the animals.

[0047] Nonvesicants typically are also irritating and can cause pain,but do not usually result in long lasting sores or ulcers or sloughingoff of tissues except in exceptional cases. Examples include alkylatingagents such as cyclophosphamide, bleomycin (blenoxane), carmustine, anddacarbazine; DNA crosslinking agents such as thiotepa, cisplatin,melphalan (L-PAM); antimetabolites such as cytarabine, fluorouracil(5-FU), methotrexate (MTX), and mercaptopurine (6 MP); topoisomerase IIinhibitors such as mitoxantrone; epipodophyllotoxins such as etoposide(VP-16) and teniposide (VM-26); hormonal agents such as estrogens,glucocorticosteroids, progestins, and antiestrogens; and miscellaneousagents such as asparaginase, and streptozocin.

[0048] A listing of materials usually accepted to be vesicants ornonvesicants is provided below as Table 1-Vesicant/Nonvesicant DrugActivity. TABLE 1 Vesicant/Non-Vesicant Drug Activity ClassificationVesicant Non-Vesicant Alkylating Agents Mechlorethamine^(a,c,d,e)Cyclophosphamide * (Cytoxan)^(b) Mitomycin-C^(a,c,e)* Bleomycin(Blenoxane)^(b,e) Dactinomycin^(d,e)* Carmustine^(a,b,d) Mithramycin^(d)Mithramycin^(a,b) (Plicamycin) (Plicamycin) Dacarbazine^(a,b,e) DNACrosslinking Thiotepa^(b) Agents Cisplatin^(b,e) Melphalan (L-PAM)^(b)Antimetabolites Cytarabine (ARA C)^(b) Fluorouracil (5 FU)^(b,d,e)Methotrexate (MTX)^(b) Mercaptopurine (6 MP)^(b) Topoisomerase IIBisantrene^(c,e)* Mitoxantrone^(b,e) Inhibitors (Anthracene)(Anthracene) Dactinomycin^(a,c) Esorubicin^(e) Doxorubicin^(a,b,c,d,e)*Etoposide (VP-16)^(a,b,e) (Anthracycline) (Epipodophyllotoxin)Cyanomorpholinyl Teniposide (VM-26)^(a,b,e) Doxorubicine*(Epipodophyllotoxin) Amsacrine^(a,c,e)* Epirubicin^(c,e)*Daunorubicin^(a,d,e)* Idarubicin^(a,e)* Liposomal anthracyclines^(e)Hormonal Agents Estrogens^(b) Glucocorticosteroids^(b) Progestins^(b)Antiestrogens^(b) Tubulin Inhibitors Vinblastine^(a,d,e)*Vincristine^(a,d,e)* Vinorelbine^(e)* Vindesine^(a,e)* Paclitaxel^(c,)Pacitaxele^(e,f) Miscellaneous Asparaginase^(b) (Enzyme)Aclacinomycin^(e) Streptozocin^(a,b) Menogaril^(e)

[0049] a—According to U.S. Pat. No. 5,602,112

[0050] b—Dorr, R. T. et al, Lack of Experimental Vesicant Activity forthe Anticancer Agents Cisplatin, Melphalan, and Mitoxantrone, CancerChemother. Pharmacol., Vol. 16, 1986, pp. 91-94

[0051] c—According to Bicher, A. et al, Infusion Site Soft-Tissue InjuryAfter Paclitaxel Administration, Cancer, Vol. 76, No. 1, July 1, 1995,pp. 116-120

[0052] d—Rudolph, R. et al; Etiology and Treatment of ChemotherapeuticAgent Extravasation Injuries: A Review; Journal of Clinical Oncology,Vol. 5; No. 7; July 1987; pp. 1116-1126

[0053] e—Bertelli, G., Prevention and Management of Extravasation ofCytotoxic Drugs, Drug Safety, 12 (4) 1995; pp. 245-255. The listed drugshave been reported in at least one case, either clinically orexperimentally, to cause tissue necrosis after accidental extravasation.Symbol: *=vesicants, drugs with the highest potential for localizedtissue damage after extravasation

[0054] f—Cancer, R.T., Communications, Author Reply, Cancer, pp. 226

[0055] Typical embodiments of the invention use highly toxicantineoplastic drugs that have similar or greater vesicating activitythan those that have been tested in animals by inhalation to date. Oneembodiment typically uses severely vesicating toxic antineoplastic drugshaving higher vesicating activity than those represented by 5-FU,β-cytosine arabinoside (Ara-C, cytarabine), mitomycin C, and cisplatin.In respect to the latter, it is disclosed that a highly toxic drugrepresented by the class anthracyclines (of which doxorubicin is amongthe most toxic), has been administered by inhalation to a patient inneed of treatment for neoplasms. In a further embodiment of theinvention it is disclosed that vesicants other than doxorubicin can begiven to patients by inhalation. In respect to the latter, highly toxicdrugs represented by the classes vinca alkaloids, and taxanes, havingsimilar high toxicities have been administered by inhalation to apatient in need of treatment for neoplasms. In a yet further embodimentof the invention there is disclosed that certain antineoplastic drugsthat are nonvesicants can be administered by inhalation to a patient inneed of treatment for neoplasms. In a further embodiment of theinvention there are disclosed formulations and methods for applying theaforementioned highly toxic drugs to a patient in need of treatment forpulmonary neoplasms by inhalation.

EXAMPLE 1

[0056] This example illustrates and confirms toxicity andvesicant/nonvesicant activity of several antineoplastic drugs. Thevesicant activities of thirteen anticancer drugs were investigated (seethe listing in Table 2 below). Doxorubicin has traditionally beenconsidered a vesicant (see Table 1). Paclitaxel has previously beenconsidered a nonvesicant, but recent literature has advocated itsclassification as a vesicant. Some of the remaining drugs aretraditionally considered to be vesicants and others nonvesicants (Table1). Day fourteen after injection was chosen as the time for comparisonfor vesicant activity, because lesions caused by nonvesicants shouldhave been significantly reduced while lesions caused by vesicants shouldstill be large. Sterile saline solution (0.9%) for injection USP, pH4.5-7.0, or sterile water for injection, as appropriate, was used toreconstitute the drugs.

[0057] The drugs used for the vesicant activity tests are identified asfollows: doxorubicin (Adriamycin PFS), a red liquid in glass vials, noformulation was necessary; cisplatin (Platinol-AQ™), a liquid in glassvials, no formulation was necessary; Paclitaxel (Taxol™), a liquid inglass vials, formulated with saline solution; fluorouracil, a clearyellow liquid in glass vials, no formulation was necessary; cytarabine(Cytosar-U™), a white powder in glass vials, formulated with water;9-aminocamptothecin (9-AC colloidal suspension), a yellow powder inglass vials, formulated with water; cyclophosphamide (Cytoxan™), ayellow powder in glass vials, formulated with a saline/water mixture;carboplatin (Paraplatin™), a white powder in injectable vials,formulated with saline solution; etoposide (VePesid™), a clear liquid inglass vials, formulated with saline solution; bleomycin (bleomycinsulfate, USP), a lyophilized powder tablet in glass vials, formulatedwith saline solution; vincristine (vincristine sulfate), an injectableliquid in injection vials, no formulation necessary; vinorelbinetartrate (Navelbine™), a clear liquid in glass vials, diluted with waterper package instructions; and mitomycin (Mutamycin™), a gray crystallinepowder in glass amber bottles, formulated with water. All of these drugswere reconstituted following standard and known methods recommended bythe manufacturers.

[0058] The tests for vesicant activity were conducted using SpragueDawley rats (7-8 weeks old having 150-200 g of body weight. Eachreceived a single intradermal injection of the test drug at therecommended clinical concentration (listed below in Table 2) in theright dorsum. Approximately 24 hours prior to administration, the hairwas removed from the dorsum using clippers and a depilatory agent. Each0.2 ml injection was given with a 1 ml syringe and 27 gauge needle. Alldrug solutions were either isotonic or slightly hypertonic. TABLE 2Formulations administered for Vesicant Tests Formulation TestFormulation Concentration 1 Doxorubicin 2 mg/ml 2 Platinol 1 mg/ml 3Paclitaxel 1.2 mg/ml 4 Fluorouracil 50 mg/ml 5 Cytarabine 100 mg/ml 69-aminocamptothecin 100 mg/ml 7 Cyclophosphamide 20 mg/ml 8 Carboplatin10 mg/ml 9 Etoposide 0.4 mg/ml 10 Bleomycin 20 units/ml 11 Vincristine 1mg/ml 12 Vinorelbine 3 mg/ml 13 Mitomycin-C 0.5 mg/ml

[0059] Table 3 below is a tabulation of the resultant lesion sizes thatdeveloped from intradermal injections of the above drugs. Lesion sizeswere measured as more fully discussed below. TABLE 3 Individual LesionSize Measurements (mm²) (see text for explanation of measurements)Animal Day of Test (post injection) Number Test Drug 6 8 10 13 15 17 2022 24 27 29 31 34 36 38 41 101 Doxorubicin — 21.4 33.9 57.0 42.9 34.035.4 27.2 32.2 31.7 31.7 17.1 8.3 6.3 6.7 4.5 102 Doxorubicin — 18.823.5 10.9 12.9 9.7 10.2 9.9 11.8 10.5 9.9 10.2 2.8 — — — 103 Doxorubicin— 36.5 58.0 82.9 45.5 37.7 28.1 26.9 21.0 23.9 18.6 16.2 12.5 10.3 7.66.1 104 Doxorubicin — 44.6 27.3 33.6 17.7 21.7 28.1 19.5 16.6 16.1 18.913.9 9.0 5.1 4.5 4.0 105 Doxorubicin — 33.9 35.2 33.3 35.1 29.4 30.229.7 25.0 24.4 24.8 23.5 24.0 24.5 21.6 22.0 106 Doxorubicin — 30.6 43.232.2 35.2 34.4 29.2 30.2 15.5 16.0 15.4 14.5 16.2 14.8 14.3 5.2 107Doxorubicin — 26.1 39.7 38.6 33.8 31.3 25.0 22.0 21.6 19.8 22.4 21.520.9 21.0 18.4 18.9 111 Platinol 26.9 18.7 18.0 11.8 21.2 17.1 6.9 1.51.0 — — — — — — — 112 Platinol 35.5 20.3 20.8 15.5 16.1 16.2 16.5 4.1 —— — — — — — — 113 Platinol 15.3 15.8 14.6 10.1 9.1 9.0 8.3 2.9 2.6 1.7 —— — — — — 114 Platinol 17.2 11.3 13.2 9.7 9.2 10.3 10.5 9.1 — — — — — —— 115 Platinol 26.8 25.0 14.8 21.8 18.0 15.0 16.0 16.0 2.1 1.7 1.4 — — —— — 116 Platinol 21.8 20.7 12.2 11.8 12.9 12.6 8.4 10.8 8.5 8.4 — — — —— — 117 Platinol 24.9 21.3 16.7 15.1 16.4 14.8 14.3 12.2 12.5 2.8 — — —— — — 121 Taxol 23.7 21.6 21.2 18.9 3.5 — — — — — — — — — — — 122 Taxol37.3 30.1 26.1 25.2 21.8 21.7 5.6 2.1 1.8 — — — — — — — 123 Taxol 7.95.9 4.3 1.1 1.2 — — — — — — — — — — — 124 Taxol 43.2 36.9 32.9 30.6 29.028.5 — — — — — — — — — — 125 Taxol 38.4 34.6 28.6 22.1 5.9 — — — — — — —— — — — 126 Taxol 69.5 59.5 53.3 53.3 42.9 5.2 — — — — — — — — — — 127Taxol 45.9 23.1 16.1 14.3 8.4 5.0 — — — — — — — — — — 131 Fluorouracil29.0 19.9 13.5 11.2 14.3 11.6 8.3 2.0 — — — — — — — — 132 Fluorouracil17.1 16.2 11.8 3.0 — — — — — — — — — — — — 133 Fluorouracil 27.0 23.817.4 17.6 17.9 0.5 — — — — — — — — — — 134 Fluorouracil 21.9 18.9 17.06.7 — — — — — — — — — — — — 135 Fluorouracil 20.5 27.5 21.4 4.5 — — — —— — — — — — — — 136 Fluorouracil 23.5 14.0 10.1 9.5 8.0 7.8 1.8 — — — —— — — — — 137 Fluorouracil 20.5 7.0 6.2 4.8 4.6 3.8 — — — — — — — — — —151 9-aminocamptothecin 21.8 15.8 16.0 14.5 9.0 19.9 — — — — — — — — — —152 9-aminocamptothecin 8.6 4.4 5.4 3.7 4.0 3.6 — — — — — — — — — — 1539-aminocamptothecin 4.4 2.6 2.9 1.3 1.1 — — — — — — — — — — — 1549-aminocamptothecin 23.8 21.9 20.9 19.8 15.5 18.6 — — — — — — — — — —155 9-aminocamptothecin 12.5 7.9 10.0 9.6 9.9 0.6 — — — — — — — — — —156 9-aminocamptothecin 12.6 10.4 5.8 4.6 3.1 — — — — — — — — — — — 1579-aminocamptothecin 12.5 7.8 5.2 3.7 — — — — — — — — — — — — 161Cyclophosphamide 16.4 13.6 11.3 9.4 8.3 8.6 — — — — — — — — — — 162Cyclophosphamide 35.1 33.8 23.2 3.5 1.4 — — — — — — — — — — — 163Cyclophosphamide 25.8 18.9 21.0 19.3 17.2 17.2 12.1 12.5 14.0 7.8 2.4 —— — — — 165 Cyclophosphamide 19.4 18.2 17.9 17.4 16.6 15.9 13.2 12.212.7 7.5 1.8 1.5 — — — — 166 Cyclophosphamide 31.8 33.8 25.4 23.9 11.92.2 — — — — — — — — — — 167 Cyclophosphamide 25.2 19.7 19.1 19.3 18.918.9 17.4 14.6 15.6 4.1 2.0 — — — — — 171 Carboplatin 16.2 17.3 12.210.9 10.4 8.1 4.6 0.8 — — — — — — — — 172 Carboplatin 9.0 5.1 21.9 17.57.6 4.1 5.2 6.2 5.9 5.2 3.2 2.6 — — — — 173 Carboplatin 24.8 23.4 17.720.5 18.5 16.0 8.6 3.4 0.8 0.6 — — — — — — 174 Carboplatin 31.9 23.118.2 24.2 27.0 19.4 15.5 13.1 11.2 4.0 1.5 — — — — — 175 Carboplatin20.5 24.5 22.1 13.4 20.4 16.8 5.4 4.9 1.8 1.2 — — — — — — 177Carboplatin 42.9 39.1 30.1 31.7 32.7 32.6 35.4 34.7 34.6 23.9 25.2 25.719.2 0.6 — — 181 Etoposide 21.1 15.0 11.2 9.2 9.8 9.0 2.9 — — — — — — —— — 182 Etoposide — — 3.8 2.4 2.0 1.7 1.1 — — — — — — — — — 183Etoposide 1.3 4.6 3.1 2.9 3.8 1.2 — — — — — — — — — — 184 Etoposide —9.6 4.7 — — — — — — — — — — — — — 185 Etoposide 5.9 6.0 6.0 2.6 2.1 2.0— — — — — — — — — — 186 Etoposide 10.6 14.1 7.7 6.6 8.4 3.8 1.7 — — — —— — — — — 187 Etoposide 6.5 10.0 9.3 5.3 5.4 5.1 3.5 — — — — — — — — —191 Bleomycin 8.2 5.1 8.8 2.2 1.6 — — — — — — — — — — — 192 Bleomycin21.1 15.3 10.8 16.3 3.8 1.3 — — — — — — — — — — 193 Bleomycin 23.5 18.915.4 13.8 5.5 1.3 — — — — — — — — — — 194 Bleomycin — 5.0 3.2 1.0 2.3 —— — — — — — — — — — 195 Bleomycin 7.7 6.5 6.7 6.5 7.0 3.2 1.3 — — — — —— — — — 196 Bleomycin 13.4 7.8 6.8 7.2 6.6 0.7 — — — — — — — — — — 197Bleomycin 27.0 27.0 26.0 25.2 26.0 24.0 1.0 0.6 — 0.4 — — — — — — 202Vincristine — — 469.0 307.7 227.7 160.5 109.2 93.3 93.6 83.6 67.2 57.947.5 40.3 40.2 34.0 203 Vincristine — — — 165.3 158.5 67.0 29.7 28.624.7 21.1 22.0 22.8 27.5 30.6 21.2 13.8 205 Vincristine — — — 130.4136.2 111.6 76.1 61.5 58.0 42.0 26.5 18.1 12.6 5.3 4.2 1.3 206Vincristine — — 145.6 96.9 81.6 96.1 66.7 59.2 51.3 13.0 7.2 — — — — —211 Vinorelbine — 16.8 421.7 315.2 289.7 274.6 250.8 200.8 170.8 159.1237.2 243.6 243.1 219.4 180.6 149.0 212 Vinorelbine — 436.7 422.1 426.5408.5 347.6 316.8 298.8 292.4 282.0 251.0 81.3 82.0 83.8 45.8 17.2 213Vinorelbine — 402.2 429.0 352.6 323.4 372.9 366.3 311.6 312.1 299.2302.3 294.0 102.7 137.7 212.1 192.1 214 Vinorelbine — 322.1 261.6 283.6293.9 241.7 227.0 221.9 227.2 105.0 86.1 72.5 65.3 71.4 52.5 62.0 215Vinorelbine — 297.0 277.8 269.7 225.3 204.2 82.5 69.8 67.8 40.0 28.431.9 17.4 19.2 14.0 14.5 216 Vinorelbine — 348.3 325.1 308.1 288.9 297.0278.7 255.9 269.3 255.8 134.9 103.7 61.2 95.7 123.2 108.2 217Vinorelbine — 275.1 309.6 272.1 249.0 217.1 208.1 209.3 190.7 175.5173.2 172.0 173.4 157.3 187.7 155.5 221 Mutamycin 45.0 46.8 47.5 77.048.2 38.8 45.4 41.6 40.3 28.6 9.6 6.4 4.1 0.7 — — 222 Mutamycin 50.450.4 49.6 41.9 45.1 34.8 42.0 46.2 9.9 9.3 7.5 — — — — — 223 Mutamycin98.3 73.0 79.1 79.8 71.0 64.6 66.0 28.5 17.6 24.3 28.2 1.1 — — — — 224Mutamycin 58.2 82.4 62.6 78.8 73.3 66.1 53.9 36.9 32.9 31.2 19.8 16.815.5 16.8 21.0 25.6 225 Mutamycin 28.1 24.2 28.0 19.8 29.8 23.0 12.813.2 11.9 8.5 6.6 7.2 2.0 1.5 — — 226 Mutamycin 61.3 53.3 59.9 49.7 48.938.0 39.5 42.1 40.6 23.0 5.6 4.8 4.6 4.6 1.2 — 227 Mutamycin 36.0 35.837.8 37.8 39.7 33.8 31.1 13.9 10.9 7.9 8.1 2.9 — — — —

[0060] Results were as follows:

[0061] 1. Abrasions of the dorsal body were observed in a majority ofanimals for all drugs except cytarabine.

[0062] 2. Alopecia of the dorsal body was seen for doxorubicin (3/7),paclitaxel (7/7), and fluorouracil (7/7), etoposide (7/7), bleomycin(7/7), vincristine (2/7), vinorelbine (7/7), and mitomycin-C (mutamycin)(4/7).

[0063] 3. Discoloration of the skin around the site of injection wasseen for doxorubicin, vincristine, vinorelbine, and mitomycin-C.

[0064] 4. Rough coat was observed in fluorouracil (1/7), vincristine(4/7), and vinorelbine (2/7).

[0065] 5. Systemic effects were observed only for vincristine. Threeanimals had to be removed from the tests because of their poorcondition.

[0066] 6. Slight edema was observed for all groups. Moderate edema wasobserved in doxorubicin, vincristine, vinorelbine, and mitomycin-Ctreated animals. Severe edema was observed only for animals treated withvinorelbine and vincristine.

[0067] 7. Severe erythema was seen for all drugs except for cisplatin(platinol) and cytarabine.

[0068] 8. Dermal lesions were observed for all drugs except forcytarabine. Most lesions appeared between days 6 and 10 and maximized insize during the first seven days, and then gradually decreased in size.Doxorubicin, vincristine, vinorelbine, and mitomycin-C were the onlydrugs that caused lesions that lasted until the test termination at day41. However, for mitomycin-C only one animal of seven still had lesionsto the end of the test. One rat (#123) injected with paclitaxel (taxol)was determined to not have received a proper intradermal injection andwas not used in the results.

[0069] Dermal lesions at the site of injection were determined to be thebest and most objective measure and predictor of vesicant activity for adrug. Lesion size was quantitated by micrometer measurements of the twolargest perpendicular diameters and the two values multiplied to yield alesion area in mm². Lesions were regularly evaluated and scored as shownin Table 3.

[0070] A vesicant as determined by the methods used herein is defined ascausing a lesion of at least about 20 mm², in at least one half of theanimals, two weeks after injection (day 15 in Table 3). Table 3 showsthat doxorubicin, paclitaxel, carboplatin, vincristine, vinorelbine, andmitomycin-C fulfill these criteria. Cisplatin, etoposide, bleomycin,cytarabine, cyclophosphamide, fluorouracil, and 9-aminocamptothecin arethus categorized as non-vesicants.

[0071] A moderate vesicant as determined by the methods used herein isdefined as causing a lesion of at least about 20 mm², in at least onehalf of the animals, two weeks after injection (day 15 in Table 3), butless than half of the animals will have lesions greater than about 10mm² 30 days after injection (day 31 in Table 3). The data from Table 3shows that paclitaxel, carboplatin, and mitomycin-C fulfill thesecriteria. Of these, mitomycin-C has been determined to exhibitsubstantial pulmonary toxicity.

[0072] A severe vesicant as determined by the methods used herein isdefined as causing a lesion of at least about 20 mm², in at leastone-half of the animals, two weeks after injection (day 15 in Table 3),and at least one-half of the animals will still have lesions greaterthan about 10 mm², 30 days after injection (day 31 in Table 3). Table 3shows that doxorubicin, vincristine, and vinorelbine satisfy thesecriteria.

[0073] Surprisingly it has now been found that moderate to severevesicants can be used for inhalation therapy of cancer as revealed inthe discussion and examples below. Further, other highly toxic drugs,although not having the severity of reaction of moderate to severevesicants have also been found to be useful in the treatment of cancerby inhalation as further discussed below.

[0074] Antineoplastic drugs that are highly toxic and useful in anembodiment of the present invention include the anthracyclines (e.g.doxorubicin, epirubicin, idarubicin, methoxy-morpholinodoxorubicin,daunorubicin, and the like); vinca alkaloids (e.g. vincristine,vinblastine, vindesine, and the like); alkylating agents (e.g.mechlorethamine and the like); carboplatin; nitrogen mustards (e.g.melphalan and the like), topoisomerase I inhibitors (e.g.9-aminocamptothecin, camptothecin, topotecan, irenotecan,9-NO-camptothecin, and the like); topoisomerase II inhibitors (e.g.etoposide, teniposide, and the like); and paclitaxel and the like. Theseand other useful compounds are further discussed below.

[0075] In yet a further embodiment of the invention, there are disclosedformulations and methods for applying an appropriate selection of highlytoxic drugs that are efficacious in treating the neoplasm or cancer,that are applied by inhalation and that reside in the pulmonary systemfor a time sufficient to increase the exposure of the neoplasm to thedrug, yet allow a reduction and/or controlled systemic exposure of thedrug, and provide a more efficacious treatment for pulmonary neoplasms.

[0076] In a further embodiment of the invention, it is disclosed that itis possible to deliver antineoplastic drugs by the pulmonary route as ameans to provide systemic treatment of distant tumors. The inventorshave shown that for selected drugs inhalation can be used as anoninvasive route of delivery without causing significant toxicity tothe respiratory tract. This is in contrast with the prior art that usedinhalation for treatment of disease in the respiratory system.

[0077] As used herein the term patient includes a mammal including, butnot limited to, mice, rats, cats, horses, dogs, cattle, sheep, apes,monkeys, goats, camels, other domesticated animals, and of coursehumans.

[0078] Administration by inhalation as used herein includes therespiratory administration of drugs as either liquid aerosols orpowdered aerosols suspended in a gas such as air or other nonreactivecarrier gas that is inhaled by a patient. Non-encapsulated drug as usedherein means that the antineoplastic drug is not enclosed within aliposome, or within a polymeric matrix, or within an enclosing shell.Where the term encapsulated drug is used herein the term means that theantineoplastic drug is enclosed within a liposome, within a polymericmatrix, or within an enclosing shell. However, in some embodiments theantineoplastic drug may be coupled to various molecules yet is still notenclosed in a liposome, matrix or shell as further discussed below.

[0079] In other embodiments of the invention the antineoplastic drugsdisclosed herein may be coupled with other molecules through esterbonds. Enzymes present in the respiratory system later cleave the esterbonds. One purpose of coupling the antineoplastic drugs through an esterbond is to increase the residence time of the antineoplastic drug in thepulmonary system. Increased residence time is achieved by: first, anincrease in molecular weight due to the attached molecule; second, byappropriate choice of a coupled molecule; third, other factors such asfor example charge, solubility, shape, particle size of the deliveredaerosol, and protein binding can be modified and used to alter thediffusion of the drug. Molecules useful for esterification with the druginclude alpha-hydroxy acids and oligomers thereof, vitamins such asvitamins A, C, E and retinoic acid, other retinoids, ceramides,saturated or unsaturated fatty acids such as linoleic acid and glycerin.Preferred molecules for esterification are those naturally present inthe area of deposition of the active drug in the respiratory tract.

[0080] As a demonstration of the proof of concept, doxorubicin was usedin a series of tests. Doxorubicin was chosen as an initial test agentsince it is one of most cytotoxic and potent vesicants of allanti-neoplastic agents considered in the broad embodiment (pulmonarydelivery of anti-neoplastic drugs) of the present invention. Based onpositive outcome of these proof of concept studies, anticancer drugsfrom other major classes were simultaneously tested. Resultsconsistently showed that using the approach and methods described inthis invention the drug could be safely and effectively delivered byinhalation. In Examples 2 and 3 below, doxorubicin was administered tothree dogs (beagles) by both the pulmonary and intravenous route ofadministration. The dogs were given a clinically effective dosage of thedrug and the amount of the drug appearing in the blood system wasmeasured.

[0081] An anthracycline antineoplastic drug, a salt of doxorubicin,doxorubicin HCl, available from Farmitalia Carlo Erba (now Pharmacia &Upjohn), Milan, Italy, was used in some of the examples herein. Theliquid formulation that was administered to the dogs by inhalation of anaerosol was obtained by mixing the doxorubicin hydrochloride with amixture of ethanol/water at a doxorubicin concentration of approximately15-25 mg/ml. Typically solutions of 5-75% ethanol are preferred.Water/ethanol ratios may be adjusted to select the desired concentrationof doxorubicin and the desired particle size of the aerosol.

EXAMPLE 2

[0082] Three adult, male, beagle dogs were used in the tests. The dogs(designated dog 101, 102, and 103) had body weights of 10.66, 10.24, and10.02 kg respectively . As used herein “m²” used alone with reference todose refers to square meters in terms of the body surface area of atreated animal or patient, at other times it is qualified in terms oflung surface area. The dogs were given a slow IV infusion treatment ofthe anthracycline drug doxorubicin HCl at the recommended initialclinical dose (for dogs) of 20 mg/m² or 1 mg/kg of body weight. A 1mg/ml drug solution was administered at a rate of 2.0 ml/kg/hr for 30minutes. The 30-minute infusion interval simulated the time/doseexposure relationship of the inhalation group in Example 3 below. Aseries of blood samples were taken to characterize the IVpharmacokinetics at predose, 2, 5, 10, 30, 60, 90 minutes and 2, 4, 6,12, 18, and 36 hours post dosing. Additional blood samples werecollected for clinical pathology evaluations on days 3 and 7 of the IVtreatment. Changes in blood chemistry and hematology were as expectedwith administration of doxorubicin HCl at these doses.

EXAMPLE 3

[0083] The three dogs used in Example 2 were allowed a one-week washoutperiod before being subjected to exposure to the anthracycline drugdoxorubicin HCl by inhalation. The dogs were acclimated to wearing masksfor administration of the aerosol prior to treatment. The dogs wereexposed to an aerosol concentration of drug sufficient to deposit atotal dose of about 10 mg (1 mg/kg). Based on aerosol dosimetry models,approximately one half of this dose was deposited within the respiratorytract. The total dose was about equal to the dosage administered by IVinfusion. The dose was calculated using the following equation:

Dose={Drug Conc. (mg/liter)×Mean minute Vol. (liter/min)×ExposureDuration (min)×Total Deposition Fraction (%)}÷Body Weight (kg)

[0084] wherein

[0085] Mean Min. Vol.=Tidal volume×minute respiratory rate

[0086] Exposure Duration=30 min

[0087] Mean Body Weight=weight in kg for each dog

[0088] Total Deposition Fraction=60% (determined by particle size andrespiratory tract deposition models from the published literature suchas “Respiratory Tract Deposition of Inhaled Polydisperse Aerosols inBeagle Dogs”, R. G. Cuddihy et al, Aerosol Science, Vol 4, pp. 35-45(1973) and “Deposition and Retention Models for Internal Dosimetry ofthe Human Respiratory Tract”, Task Group on Lung Dynamics, HealthPhysics, Vol. 12, pp. 173-207 (1966).

[0089] Pulmonary function measurements (respiratory rate, tidal volume,and minute volume (calculated)) were monitored during a 30 minuteinhalation exposure session. These data provided an estimate of eachanimal's inspired volume during exposure, and were used to calculate themass of drug deposited in the respiratory tract.

[0090] A series of blood samples were collected at the end of theexposure to characterize the pharmacokinetics. Clinical pathologyevaluations were conducted on the third day. All three dogs werenecropsied on the third day.

[0091] Referring now to FIG. 4, the drug formulation was administered tothe dogs of Example 3 with drug exposure system 400. The drug wasaerosolized with two Pari LC Jet Plus™ nebulizers 401. The nebulizer wasfilled with a solution of 15 mg doxorubicin per ml of 50% water/50%ethanol. The output of each nebulizer 401 was continuous and set toprovide the required concentration of aerosol in attached plenum 405.The nebulizers 401 were attached directly to plenum 405 that had avolume of approximately 90 liters . Plenum 405 was connected by fourtubes 407 to four venturi 409, respectively, and subsequently connectedto four Y-fittings 413 by additional tubing 411. Typical venturi wereused to measure the inhaled volume of drug formulation. One end of eachof the Y-fittings 411 interfaced with a dog breathing mask 415 while theother end of Y-fitting 411 was connected to tubing 417 leading to anexhaust pump 419. During the tests three dogs 418 were fitted with threeof the breathing masks 415. A collection filter 421 was placed in theremaining mask 415. A vacuum pump 423 that drew 1 liter per minute ofair for 3 minutes was used in the place of a dog to draw aerosol inorder to monitor and measure the amount of drug administered. The vacuumpump was activated four times during the 30-minute administration ofdrug to the dogs and the amount of drug trapped by the filter set forthin Table 5 below.

[0092] A flow of air was supplied to each of the nebulizers 401 from asupply of air 425 via lines 427. Additional air for providing a biasflow of air through the system and for the breathing requirements of thedogs was provided from air supply 425 by supply lines 429 connected toone way valves 431. The one way valves 431 were connected to the upperportion of the nebulizers 401. This additional supply of air provided acontinuous flow of air through the system 400 from the air supply 425 tothe exhaust pump 417. Alternatively one could eliminate the extra supplyof air from supply lines 429 to one way valves 431 and let ambient roomair enter the one way valves from the suction action of the nebulizers401. A Hepa filter 441 mounted to the top of plenum 405 allowed room airto flow in and out of plenum 405 and assured that there was alwaysambient pressure in the plenum. There was a continuous flow of aircontaining the aerosol past the masks of the dogs and the dogs were ableto breathe air containing the aerosol on demand. An inner tube 621located within dog breathing mask 415 extended into the mouth of thedogs and was provided with an extension 633 at its lower portion thatserved to depress the tongue of the dogs to provide an open airway forbreathing. See the discussion of FIG. 6 below.

[0093] Each of the four venturi 409 were connected by line 441 to apressure transducer 443 (the one shown is typical for the four venturi)that was used to measure pressure differences across the venturi. Thepressure transducers 443 were connected by line 445 to an analogamplifier 447 to increase the output signal and prepare the signal sentvia line 449 to computer system 451. Computer system 451 is a desk modelPC of typical design in the industry and can be used in conjunction witha BUXCO or PO-NE-MAH software program to calculate the uptake of aircontaining aerosol and thus the drug dosage by each of the dogs.

[0094] Table 4 below summarizes the exposure data for doxorubicinadministration to dogs from Example 3. The total mass for each dog wasdetermined. The total inhaled volume of air for the 30 minute drugadministration was measured in liters. The aerosol concentration in mgof drug/liter of air (mg/l) was determined from calibration tests doneearlier. A total deposition fraction of 60% was calculated (Ascalculated 30% for the inhaled dose was deposited in the conductingupper airways and peripheral lung while and additional 30% was depositedin the oral-pharyngeal region) based on the measured doxorubicin aerosolparticle size and the published literature (see references cited above).

[0095] Thus about 25%-30% of the administered doxorubicin was depositedand available to the pulmonary region. Since the drug was administeredin its salt form, a correction for the chlorine portion of the moleculewas made. As shown in the Table 4 this resulted in an applied dose of0.51, 0.60, and 0.57 mg/kg to the pulmonary region of dogs 101, 102, and103 respectively

[0096] Filter data obtained from analysis of drug deposited on a filter421 placed in a fourth mask 415 are shown in Table 5 for four differentmeasurements . The drug mass collected on the filter was corrected forthe chlorine portion of the doxorubicin salt. Finally, the doxorubicinconcentration in the three liters of air drawn into each mask wasdetermined in mg/l. The four figures were averaged to obtain a meandoxorubicin aerosol concentration of 0.218 mg/l.

[0097] Table 6 shows data and calculations that verify the figures ofTable 4. The dog weight and breath volumes measured for Table 4 areused. However, the mean doxorubicin concentration that was obtained fromthe filter data shown in Table 5 was used to calculate doxorubicinconcentrations. Making calculations with the data as in Table 4, theinhaled dose for each dog was calculated. The inhaled dose was reducedby 40% as before to obtain the total dose deposited, and reduced by 50%again to obtain the total deposited pulmonary dose. The pulmonary dosesobtained by this method of 0.47, 0.56, and 0.53 mg/kg for dogs 101, 102,and 103 respectively compare well with the earlier calculated figures inTable 4. TABLE 4 TOTAL MASS DATA Total Inhaled Vol. Inhaled Air InhaledDeposited Pulmonary Dog Weight (l) Aerosol Deposition Test Art. DoseDose Dose Dog No. (kg) For 30 Min. Conc. (mg/l) Fraction Fraction(mg/kg) (mg/kg) (mg/kg) 101 10.66 77.5 0.250 0.60 0.937 1.70 1.02 0.51102 10.24 86.8 0.250 0.60 0.937 1.99 1.19 0.60 103 10.02 80.8 0.250 0.600.937 1.89 1.13 0.57 A B C D E

[0098] TABLE 5 FILTER DATA Total Dox. Sample Vol. Weight GainDoxorubicin Conc. Conc. Ratio Sample No. (liter) (mg) mass (mg) (mg/l)(mg/l) Dox/Total 1 3 0.78 × .937 0.70 0.260 0.233 0.897 2 3 0.72 × .9370.61 0.240 0.203 0.847 3 3 0.73 × .937 0.62 0.243 0.207 0.849 4 3 0.77 ×.937 0.68 0.257 0.227 0.883 Mean 0.250 0.218 0.869 A B C D

[0099] TABLE 6 ANALYTICAL DATA Total Inhaled Deposited Pulmonary DogWeight Inhaled Vol. Aerosol Dose Dose Dose Dog No. (kg) (l) Conc. (mg/l)(mg/kg) (mg/kg) (mg/kg) 101 10.66 77.5 0.218 1.58 0.95 0.47 102 10.2486.8 0.218 1.85 1.11 0.56 103 10.02 80.8 0.218 1.76 1.06 0.53 A B C

[0100] Surprisingly it was found that free non-encapsulated doxorubicinadministered by the pulmonary route was not rapidly cleared from thelung. FIGS. 1, 2 and 3 show examples of the type of results achievedwhen cytotoxic anticancer drugs were given by inhalation. Highefficiency nebulization systems as shown in FIGS. 4 and 5 were used todeliver a large percentage of aerosolized drug to the pulmonary regionof the respiratory tract. Doses equal to or greater than those thatcause toxicity when given IV, were only moderately absorbed into theblood following pulmonary delivery and caused little to no direct orsystemic toxicity after a single exposure at this dose.

[0101] As can be seen from FIGS. 1, 2 and 3, the pulmonary routeadministered doxorubicin achieved a consistently lower level ofdoxorubicin in systemic blood, with peak blood levels being over anorder of magnitude lower following inhalation exposure. The initialconcentration of doxorubicin at 2 minutes was about 1.5 orders ofmagnitude larger when administered IV than by the pulmonary route.Later, after about 4 hours, the systemic doxorubicin level was about sixtimes higher for the IV administered drug. This suggests that freedoxorubicin remained in the lung for an extended period of time andslowly passed through the mucosa into systemic circulation. This reducesthe systemic toxic effects of the drug and allows its concentration inthe lung for more effective treatment of respiratory tract associatedneoplasms while reducing overall systemic toxic effects. It is believedthat the toxic effects of doxorubicin to tissues outside the lung are asa result of the aforementioned high levels of systemic drugconcentration following IV treatment.

[0102] Another surprising finding was that doxorubicin administered bythe pulmonary route did not produce the severe toxic effects on therespiratory tract (including the oral and nasal-pharyngeal,tracheo-bronchial, and pulmonary regions). As was noted earlier,doxorubicin belongs to the anthracycline class of drugs that aretypically very toxic. In particular doxorubicin is one of the most toxicdrugs in the class, yet when the dogs in the test were necropsied, nodamage to the respiratory tract was observed. It is surprising that thedoxorubicin was not toxic to the lung when given by inhalation atclinically relevant doses such as 20 to 60 mg/m². Unlike 5-FU and Ara-C,and cisplatin, doxorubicin is well known to generate the production offree radicals (Myers et al, 1977) which are notorious for causingpulmonary toxicity (Knight, 1995). It is this property, in fact, whichis held responsible for the cardiotoxicity caused by doxorubicin givenby the intravenous route (Myers et al, 1977).

[0103] In some typical embodiments, to obtain additional benefits of thedisclosed invention for treating pulmonary neoplasms and reducingsystemic toxicity, it is important that antineoplastic drugsadministered in non-encapsulated form by the pulmonary route be absorbedinto and remain in the tumor tissue for an extended period of time anddiffuse across the lung mucosa in a relatively slow manner. In general,although solubility, charge and shape have an influence, slow diffusionis obtained by drugs having higher molecular weights while fasterdiffusion is obtained by those having relatively lower molecularweights. Thus drugs such as doxorubicin having a molecular weight of543.5, have relatively slow rates of diffusion, drugs such asvincristine (MW=825), vinblastine (MW=811), paclitaxel (MW=854),etoposide (MW=589), having higher molecular weights also diffuse slowly.Other drugs having somewhat lower molecular weights such as9-aminocamptothecin, while diffusing more slowly are still includedwithin the invention. It has been demonstrated that significantly highertissue concentrations can be achieved in the lung by pulmonary deliverycompared to conventional parenteral or oral administration. Further,systemic coverage of micrometasteses can be provided under theseconditions, with the benefit of significantly greater doses of drugdelivered to the respiratory tract tumor sites and controlled systemicexposure.

[0104] Thus in one embodiment of the invention drugs having a molecularweight above 350 are used. In this regard mitomycin-C (MW of about 334)is thus excluded from this embodiment. While molecular weight is not thesole determinant controlling diffusion through the lung it is one of theimportant factors for selecting compounds useful in the presentinvention. This lower molecular weight limit is about 64% that ofdoxorubicin. This will help assure that the limited systemicavailability of the drug discussed above is maintained. In furtherembodiments of the invention the molecular weight of the drugsadministered is above 400, 450, and 500 respectively.

[0105] In conjunction with the above discussed molecular weights,protein binding of the antineoplastic agents to be delivered bypulmonary administration should also be considered with respect todiffusion through the lung. Higher rates of protein binding will furtherslow diffusion through the lung mucosa. In this respect 5-FU and Ara-Cin addition to having low molecular weights also have relatively lowprotein binding affinity of 7% and 13% respectively. That is, whenplaced into a protein-containing solution, only 7% and 13% of thesedrugs bind to the protein while the remainder is free in solution. Inthis respect, cisplatin does not bind to tissues, rather at a laterstage it is the platinum in the cisplatin that binds to tissues, thusallowing cisplatin to enter systemic circulation as further discussedbelow. In comparison doxorubicin, vincristine, vinblastine, paclitaxel,etoposide, and 9-amino-camptothecin have rates of protein binding above50%. Typically protein-binding affinity above 25% is preferred, morepreferred is binding above 50%, with protein binding above 75% beingmost preferred when lung retention is the objective.

[0106] In a preferred formulation and method for treating neoplasms ofthe pulmonary system by inhalation, the diffusion characteristics of theparticular drug formulation through the pulmonary tissues are chosen toobtain an efficacious concentration and an efficacious residence time inthe tissue to be treated. Doses may be escalated or reduced or givenmore or less frequently to achieve selected blood levels. Additionallythe timing of administration and amount of the formulation is preferablycontrolled to optimize the therapeutic effects of the administeredformulation on the tissue to be treated and/or titrate to a specificblood level.

[0107] Diffusion through the pulmonary tissues can additionally bemodified by various excipients that can be added to the formulation toslow or accelerate the absorption of drugs into the pulmonary tissues.For example, the drug may be combined with surfactants such as thephospholipids, dimyristoylphosphatidyl choline, anddimyristoylphosphatidyl glycerol. The drugs may also be used inconjunction with bronchodilators that can relax the bronchial airwaysand allow easier entry of the antineoplastic drug to the lung. Albuterolis an example of the latter with many others known in the art. Further,the drug may complexed with biocompatible polymers, micelle formingstructures or cyclodextrins Particle size for the aerosolized drug usedin the present examples was measured at about 2.0-2.5 μm with ageometric standard deviation (GSD) of about 1.9-2.0. Typically theparticles should have a particle size of from about 1.0-5.0μm with a GSDless than about 2.0 for deposition within the central and peripheralcompartments of the lung. As noted elsewhere herein particle sizes areselected depending on the site of desired deposition of the drugparticles within the respiratory tract.

[0108] Aerosols useful in the invention include aqueous vehicles such aswater or saline with or without ethanol and may contain preservatives orantimicrobial agents such as benzalkonium chloride, paraben, and thelike, and/or stabilizing agents such as polyethyleneglycol.

[0109] Powders useful in the invention include formulations of the neatdrug or formulations of the drug combined with excipients or carrierssuch as mannitol, lactose, or other sugars. The powders used herein areeffectively suspended in a carrier gas for administration.Alternatively, the powder may be dispersed in a chamber containing a gasor gas mixture which is then inhaled by the patient.

[0110] Further, the invention includes controlling deposition patternsand total dose through careful control of patient inspiratory flow andvolume. This may be accomplished using the pulmonary devices describedherein and similar devices. The inventors have shown by gammascintigraphy measurements that drug aerosol deposition is maximized andevenly distributed in the peripheral lung when the patient inhales usingslow flow rates and inhales to maximum lung volumes followed by briefbreath holds. Central lung deposition is favored when faster inspiratoryflow rates and lower inspiratory volumes are used. Further, totaldeposited and regionally deposited doses are significantly changed as apatient's inspiratory patterns change. Therefore, the method oftreatment and the use of the delivery devices described herein can bemodified to target different regions of the respiratory tract andadjusted too deliver different doses of drug. It is the integration ofdrug molecular weight, protein binding affinity, formulation, aerosolgeneration condition, particle sized distribution, interface of aerosoldelivery to the patient via the device and the control of the patient'sinspiratory patterns that permit targeted and controlled delivery ofhighly toxic anti-cancer drugs to the respiratory tract with the optionto minimize or provide controlled systemic availability of drug.

EXAMPLE 4

[0111] The tests for administration of doxorubicin by inhalationreferred to in Example 3 were substantially repeated at differentdosages using a different drug administration system 500 describedbelow. In the present examples eight dogs were used. The dogs weredivided into two dose groups. A first group was the low dose group givena total daily dose of 60 mg/m² for three days or a total dose of 180mg/m². This resulted in a pulmonary deposition of about 90 mg/m².

[0112] A high dose group was administered a dose of 180 mg/m² daily forthree days or a total dose of 540 mg/m². This resulted in a pulmonarydeposition of about 270 mg/m².

[0113] One half of the animals were necropsied after three days ofexposure and the remaining dogs necropsied after a three day recoveryperiod.

[0114] The purpose of the tests was to identify the maximum tolerateddose of inhaled drug.

[0115] For comparison with the results of Examples 2 and 3, one canconvert the data from mg/kg to mg/m² (m² of body area) by multiplying by20 (conversion factor for the dog). Thus the exposure of the dogs inExamples 2 and 3 which were the equivalent of a clinical dose (for dogs)was about 20 mg/m². When one compares these dosages to those of Example4 (180 mg/m² and 540 mg/m²) it is apparent that a significantly higherdose of non-encapsulated drug can be delivered to the lung compared tothe known art . Although dogs receiving the lower total dose rangesshowed few toxic effects, while dogs receiving the higher total doseshad pulmonary toxicity, these doses were 9-27 times higher than thosegenerally given clinically to dogs.

[0116] While the present examples used active drug doses of doxorubicinof about 20 mg/m², 180 mg/m², and 270 mg/m², effective amounts of theactive anticancer drugs can be from very small amounts to those wheretoxicity to normal tissue becomes a problem. As used herein, effectiveamounts and pharmaceutically effective amounts of antineoplastic drugdeposited or applied to areas needing treatment are dosages that reducea neoplasm or tumor mass, stop its growth or eliminate it altogether.

[0117] Referring now to FIG. 5, the liquid formulation was administeredto the dogs by aerosolizing with a nebulizer exposure system 500comprising a Pari LC Jet Plus™ nebulizer 501. The nebulizer was filledwith the solution of drug with which the dogs were to be treated. Theoutput of the nebulizer 501 was pulsed in a series of bursts over time(one pulse every ten seconds). The nebulizer 501 was attached directlyto a 460 cc volume plenum 503 and the plenum 503 was connected to acanine mouth only exposure mask 415 via a short piece of anesthesiatubing 505 and Y-fitting 507. The mask 415 was tapered to approximatelyfit the shape of the dog's snout. There was no bias airflow through theexposure system 500. The test atmosphere was pulled through the exposuresystem 500 by the inhalation of the dog 511. A one way breathing valve513 on the top of the nebulizer 501 allowed the dog 511 to draw in roomair and pull the air through the system 500. The air entrained andtransported the aerosolized drug through the plenum 503, tubing 505,Y-fitting 507, and mask 415 to the dog 511. A one way valve 515connected to the Y-fitting 507 allowed the dog 511 to exhale and theexhaled air exited the system. An air supply 520 provided a flow of airto controller 530 via line 521. Air flow to the nebulizer was controlledby controller 530 and supplied to the nebulizer via line 531.

[0118] Referring now to FIG. 6, details of mask 415 are shown. Means forenclosing the mouth and nose are of flexible material and are preferablyheld on by straps such as Velcro™ straps or belts. Means for enclosing601 has one end 603 for inserting the nose and mouth of the dog whilethe other end 605 has two openings 607,609 for attachment of nose outlettube 611. Nose outlet tube 611 has a one way valve 613 that allows thedog to exhale but not inhale through the its nose. Mouth tube 621 isinserted and attached to opening 609 and lies within the means forenclosing 601. An optional Y-connector 623 may be attached and used withmouth tube 621 for providing and receiving inhaled and exhaled gases.Air is generally inhaled through leg 625 of the Y-connector 623. The airpasses through the mouth tube 621 and out the inner opening 631 into therespiratory system of the dog. Inner opening 631 is cut at an angle withits lower portion 633 extending further into the mouth of the dog thanthe upper portion 635. Lower portion 633 functions to depress the tongueof the dog and allow more efficient flow of air and aerosol into thedog. When the dog is wearing mask 415 it can only breathe in through itsmouth using the mouth tube 621. Means for enclosing 601 effectivelyseals the dog's mouth and nose from outside air. The use of a noseoutlet tube 611 has been found to greatly ease the dogs wearing of themask. Air exhaled through the mouth exits mouth tube 621 and passes intooptionally attached Y-connector or to another tube not shown. Air exitsY connector 623 via outlet tube 627. If desired the Y-connector 623 orother outer tube (e.g. straight tubing) may be made of one piece andsimply pass into the enclosing means 601 or may be of separate piecesthat fit together. In either case an adapter 637 may be used to hold themouth tube 621 and or other tubing to which it is connected.

[0119] A general device for administering aerosols to a patient includesan inhalation mask for administering aerosols to the including means forenclosing the mouth and nose of the patient, having an open end and aclosed end, the open end adapted for placing over the mouth and nose ofthe patient; upper and lower holes in the closed end adapted forinsertion of a nose outlet tube and a mouth inhalation tube; the noseoutlet tube attached to the upper hole, adapted to accept exhaled breathfrom the nose of the patient; a one way valve in the nose tube adaptedto allow exhalation but not inhalation; the mouth inhalation tube havingan outer and an inner end, partially inserted through the lower hole,the inner end continuing to end at the rear of the patients mouth, theinhalation tube end cut at an angle so that the lower portion extendsfurther into the patients mouth than the upper portion and adapted tofit the curvature of the rear of the mouth; and a y-adapter attached tothe outer end of the mouth inhalation tube.

[0120] Pulmonary administration by inhalation may be accomplished bymeans of producing liquid or powdered aerosols, for example, by thedevices disclosed herein or by using any of various devices known in theart. (see e.g. Newman, S. P., 1984, in Aerosols and the Lung, Clarke andDavia (Eds.), Butterworths, London, England, pp. 197-224; PCTPublication No. WO 92/16192 dated Oct. 1, 1992; PCT Publication No. WO91/08760 dated June 27, 1991; NTIS patent application 7-504-047 filedApr. 3, 1990 by Roosdorp and Crystal) including but not limited tonebulizers, metered dose inhalers, and powder inhalers. Various deliverydevices are commercially available and can be employed, e.g. Ultraventnebulizer (Mallinckrodt, Inc, St. Louis, Mo.); Acorn II nebulizer(Marquest Medical Products, Englewood, Colo.); Ventolin metered doseinhalers (Glaxo Inc., Research Triangle Park, N.C.); Spinhaler powderinhaler (Fisons Corp., Bedford, Mass.) or Turbohaler (Astra). Suchdevices typically entail the use of formulations suitable for dispensingfrom such a device, in which a propellant material may be present.Ultrasonic nebulizers may also be used.

[0121] Nebulizer devices such as those in Greenspan et al U.S. Pat. Nos.5,511,726 and 5,115,971 are useful in the invention. These devices useelectrohydrodynamic forces to produce a finely divided aerosol havinguniformly sized droplets by electrical atomization. While the Greenspandevices use piezoelectric materials to generate electrical power anypower source is acceptable to produce the electrohydrodynamic forces fornebulization.

[0122] A nebulizer may be used to produce aerosol particles, or any ofvarious physiologically inert gases may be used as an aerosolizingagent. Other components such as physiologically acceptable surfactants(e.g. glycerides), excipients (e.g. lactose), carriers (e.g. water,alcohol), and diluents may also be included.

[0123] As will be understood by those skilled in the art of deliveringpharmaceuticals by the pulmonary route, a major criteria for theselection of a particular device for producing an aerosol is the size ofthe resultant aerosol particles. Smaller particles are needed if thedrug particles are mainly or only intended to be delivered to theperipheral lung, i.e. the alveoli (e.g. 0.1-3 μm), while larger drugparticles are needed (e.g. 3-10 μm) if delivery is only or mainly to thecentral pulmonary system such as the upper bronchi. Impact of particlesizes on the site of deposition within the respiratory tract isgenerally known to those skilled in the art. See for example thediscussions and figures in the articles by Cuddihy et al (AerosolScience; Vol. 4; 1973, pp 35-45) (FIGS. 6, 7, and 8 of the article) andThe Task Group on Lung Dynamics (FIGS. 11 and 14 of the article). As aresult primary cancers in the naso-pharyngial or oral-pharyngeal regionsand upper tracheo-bronchial regions, often referred to as cancers of thehead and neck, are treatable with the present invention. The majormetastatic sites (lung and upper respiratory tract) are also readilytreated with this invention simultaneously, unlike current methods oftreatment.

[0124] Referring now to FIG. 7, there is disclosed a nebulizer apparatus700 that is preferably portable for administration of drug to a patientin need of therapy. The nebulizer apparatus 700 is used in combinationwith the highly toxic drugs of the present invention and with drugshaving properties adapted for optimum treatment of neoplasms asdiscussed elsewhere herein. FIG. 7 is a schematic of a nebulizercombination according to the present invention. Nebulizer 701 may be anynebulizer as described earlier herein that is able to produce theparticle sizes needed for treatment. In combination with nebulizer 701there is provided a highly toxic drug formulation 703 for treatment ofneoplasms as disclosed herein. An air supply 705 is provided either as atank of compressed gas or as a motorized pump or fan for moving air fromthe room. An optional mouthpiece 707 may be used where it is necessaryto provide sealed contact between the nebulizer and the patient.Optionally the mouthpiece 707 may be molded as part of nebulizer 701.Power for use of the nebulizer apparatus 700 may come from thecompressed gas from hand manipulation by the user or administrator or bybatteries or electrical power not shown but well known by those skilledin the art.

[0125] To control environmental contamination resulting from use of anebulizer, the patient may be placed in a well-ventilated area withexhaust air filtered to remove antineoplastic drug that escapes from thedevice.

EXAMPLES 5 to 11

[0126] Examples 5F to 11F show inhalation feasibility and proof ofconcept tests and Examples 5R to 10R show dose escalation range testswith: vesicant antineoplastic drugs including doxorubicin, paclitaxel,vincristine, vinorelbine; nonvesicant drugs including etoposide, and9-aminocampothecin (9-AC) and carboplatin. The drugs were delivered tothe pulmonary system via aerosol at a particle size of about 2 to about3 μm. The drugs were delivered in water or other vehicles appropriatefor the drug as is known in the art and as exemplified herein.

[0127] Table 7 illustrates the dosage schedule for the range-findingstudies. A minimum of 7-14 days separated each escalating dose. No rangefinding tests, only feasibility tests, were performed for mitomycin-Cand 9-AC. No feasibility tests, only dose range-finding tests, wereperformed for vinorelbine. It is important to note that the doses listedin Table 7 are the pulmonary deposited doses not the total dosesadministered.

[0128] The results of the feasibility and dose escalation studies aresummarized in Tables 7 to 11. TABLE 7 Escalating Dose Regimen forRange-Finding Studies Mean Pulmonary Deposited Dose 1^(st) 2^(nd) 3^(rd)4^(th) 5^(th) 6^(th) Example Dose Dose Dose Dose Dose Dose No. Test Drug(mg) (mg) (mg) (mg) (mg) (mg) 5R Paclitaxel 30 35 40 40 60 — 6RDoxorubicin 12 15 15 15 18 — 7R Vincristine 0.55 0.55 0.70 0.70 1.1 1.58R Vinorelbine  6 10 10 15 15 — 9R Etoposide 25 30 45 55 40 80 10R  9-AC— — — — — — 11R  Carboplatin 30 — — — — —

[0129] Animals used in Examples 5 to 11 were adult beagle dogs. For thefeasibility studies, the dogs were initially given a single intravenous(IV) dose of antineoplastic drug. This dose was given to allow acomparison of how much drug was absorbed into the blood after inhalationcompared to IV delivery. The IV dose given was typically the usual humanclinical dose that had been scaled down for the dogs based ondifferences in body mass, or the maximum tolerated dose in the dog,whichever is greater. An average human having a weight of 70kg isconsidered to have a weight to body surface ratio of 37 kg/m² and a lungsurface area of 70-100 m² of lung surface area. The average dog used inthe tests was considered to have a weight of 10kg corresponding and aweight to body surface ratio of 20 kg/m² and a lung surface area of40-50 m² lung surface area (CRC Handbook of Toxicology, 1995, CRC PressInc.). The single IV dose was used to quantify the plasma kinetics. Withmost of the cytotoxic agents treated, the single IV dose resulted in apredictable mild decrease in white blood cell counts, with no othermeasurable toxicities.

[0130] After the initial IV and before the inhalation feasibility tests,the dogs were allowed a washout period of at least seven days (until thedogs returned to normal conditions) before they were treated withinhaled antineoplastic drugs. In the inhalation feasibility tests thedogs were generally exposed to a dose of inhaled antineoplastic drug inaerosol form once per day for three consecutive days (except as noted inTables 8 to 11) and necropsied one day following the last dose with theplasma kinetics characterized after the first and third exposures. Withthe exception of cisplatin and the high dose of doxorubicin, whichcaused toxicity to the respiratory tract, the drugs did not exhibit anysignificant pulmonary toxicity in these repeated exposure inhalationfeasibility studies. In the feasibility tests the dogs used the samemask and apparatus used for the earlier examples. In the doserange-finding tests, in order to control the deposited dose, the dogswere fitted with an endo-tracheal tube and the drug administered as anaerosol directly from the endo-tracheal tube. This latter procedure madeit easier to control the pulmonary deposited dose since the aerosol wasreleased directly into the pulmonary air passages assuring deepdeposition of the drug in the lung. Also use of the endo-tracheal tubemade it possible to do the tests in a shorter time since the dogs neededa four to six week training period to properly acclimate to and use themasks. The calculated deposited doses obtained herein were verifiedexperimentally by pulmonary scintigraphy tests in dogs.

EXAMPLES 5F and 5R

[0131] Referring now to Table 8, this table shows the details of thefeasibility test of paclitaxel. Initially the dogs were administered 120mg/m² of paclitaxel by IV. After the washout period the dogs wereadministered a total deposited dose of 120 mg/m² of paclitaxel, byinhalation, three times for a total deposited dose of 360mg/m². Thisadministered dose resulted in a pulmonary deposited dose of about 27 mgeach time or a total pulmonary dose of about 81 mg. This represents atotal pulmonary deposited dose of about 2.1 mg/m² of lung surface area.The dosages were calculated as follows: the dose of 120 mg/m² wasdivided by 20 kg/m² to yield a 6 mg/kg dose that was multiplied by 10 kgfor the average dog to yield about 60 mg of drug. Since the dogs wereusing the masks for drug administration, one half or about 30 mg of drugwas considered deposited in the deep lung. Since the drug wasadministered three times the total drug exposure was about 90 mg. The 90mg of drug was divided by 40 to yield a total dose to the lung of about2.25 mg/m² lung surface area.

[0132] The clinical condition of the dogs was normal. Clinical pathologyprofiles were normal with only mildly reduced white blood cell counts.The histopathology showed bone marrow and lymphoid depletion, GI villousatrophy and congestion and laryngeal inflammation. These changesindicated that some significant fraction of the deposited drug wasabsorbed systemically. There was no respiratory tract toxicity found.Bioavailability of the paclitaxel was found to be low to moderate basedon plasma kinetic evaluations. The low to moderate bioavailabilityindicates that most of the paclitaxel remained in the lungs and did notrapidly enter systemic circulation in large amounts. Therefore, giventhe lack of significant direct respiratory tact toxicity, the probabledose limiting toxicity is considered to be myelosuppression and/or GItoxicity. Thus factors extrinsic to the lung are expected to limitdosages provided by the pulmonary route.

[0133] Referring again to Tables 7 and 8, in the range-finding tests 60to 120 mg/m² of paclitaxel were administered at weekly intervals forfive weeks. The amount of pulmonary deposited dose ranged from about 30to about 60 mg. This range corresponded to about 0.75 to about 1.50mg/m² lung surface area. The clinical conditions of these dogs werenormal, with clinical pathology changes limited to moderate white bloodcell count reduction. The histopathology showed thoracic and mesentericlymphoid depletion along with GI inflammation and ulceration. Thehistopathology reflects that normally found in IV administration ofpaclitaxel particularly GI inflammation and ulceration which is probablyassociated with systemically administered paclitaxel. Respiratory tracttoxicity indicated minimal pulmonary interstitial inflammation. Systemicbioavailability was proportional to dose. The probable dose limitingtoxicity is myelosuppression and GI toxicity, and not pulmonarytoxicity. TABLE 8 Paclitaxel Summary Results of Dog Feasibility and DoseRange-Finding Studies Probable Pulmonary Respiratory Dose- IV InhalationDeposited Clinical Clinical Tract Limiting Chemotherapy dose Dose DoseCondition Pathology Histopathology Toxicity Bioavailability ToxicityExample 5F 120 120 30 mg × 3 Normal ↓ WBC Bone marrow None Low-moderateMyelo- Paclitaxel mg/m² mg/² × 3 doses & lymphoid suppressio Feasibility(360 depletion n GI mg/m² GI villous toxicity total) Atrophy &congestion Laryngeal inflammation Example 5R NA 60-120 30-60 mg Normal↓↓ WBC Thoracic and Minimal Proportional Myelo- Paclitaxel mg/m² (5 perdose mesenteric pulmonary to dose suppressio Dose Range- wkly Rx)lymphoid interstitial n GI Finding depletion inflamma- toxicity GI tioninflammation and ulceration

EXAMPLES 6F and 6R

[0134] Referring now to Table 9, 20 mg of doxorubicin were initiallyadministered by IV. After the washout period three sets of inhalationfeasibility tests were made. In the first, a single dose of 20 mg/m² ofdoxorubicin was administered that gave about a 10 mg body dose, apulmonary deposited dose of aboutS mg or about 0.125 mg/m² lung surfacearea. No changes were noted in the animal from this dose. A second setof moderate inhalation dosages of about 40 mg/m² of doxorubicin (about10 mg deposited within the lung) was administered three times a day forthree consecutive days. Total cumulative dose administered was 120 mg/m²corresponding to a about a 60 mg body dose, and a total pulmonarydeposited dose of about 30 mg (or about 0.75 mg/m² of lung surfacearea). A third set of high inhalation dosages of 120 mg/m² ofdoxorubicin was administered three times per day over a three day periodfor a total dose of 360 mg/m² corresponding to a 180 mg body dose, atotal pulmonary deposited dose of about 90 mg or about 2.25 mg/m² oflung surface area. One half of the low dose group dogs was necropsiedthe day after the final exposure and the remaining half was necropsiedfour days later. All high dose dogs were necropsied the day after thefinal exposure.

[0135] Exposure to these extremely high doses resulted in the death ofone high dose group dog after three days of exposure with the remainingthree dogs euthanized in moderately debilitated to moribund conditions.This dose intensive treatment caused pulmonary edema, a sequela ofmicroscopically recognizable degeneration, necrosis and inflammation ofepithelial surfaces lining the bronchials and larynx and the mucosalsurfaces of the nose and lips. These lesions were life threatening andmore severe in the high dose group, but were considered survivable atthe lower dose, based on the clinical condition of the animals. Despitethese higher doses, there were no clinical pathology changes indicativeof doxorubicin induced myelosuppression. There was microscopic evidenceof lymphoid depletion in the regional lymph nodes of the respiratory andgastrointestinal tracts suggestive of regional drainage of freedoxorubicin to the draining lymph nodes of the thoracic and GI systems.WBC values actually increased in the high dose group, a changeassociated with the inflammatory response observed in the respiratorytract. There were no other clinical pathology changes of note other thanincreased serum alkaline phosphatase in the high dose group, anonspecific change, due likely to respiratory tract tissue damage.

[0136] Generally, changes noted at the moderate and high dosages wereedema, increased white blood cell count and increased respiratory rate.Histopathology revealed thoracic and GI lymphoid depletion for themoderate and higher doses, respectively. Respiratory tract toxicityincluding airway epithelial degeneration and moderate to severeinflammation was noted at the increased dosages. Bioavailability was lowto moderate indicating an absorption rate limiting process in movementof the drug into the systemic circulation. The probable dose limitingtoxicity of doxorubicin is expected to be respiratory tract toxicityrather than a systemic toxicity.

[0137] In addition, a dose escalation study was conducted on a weeklyexposure schedule. Initial doses of 12 mg deposited were delivered viaendotracheal tube to the lungs, with a 5^(th) weekly dose of 18 mgdeposited within the lungs. This provided a total body dose of 24 to 36mg/m². The results of this repeated dose trial were similar in character(but not in severity) to the higher dose tests. Animals survived thistreatment regimen with minimal clinical evidence of toxicity and noevidence of systemic changes. Histologically, there was no evidence ofrespiratory tract epithelial degeneration and inflammation. TABLE 9Doxorubicin Summary Results of Dog Feasibility and Dose Range-FindingStudies Probable Pulmonary Respiratory Dose- Inhalation DepositedClinical Clinical Tract Limiting Chemotherapy IV dose Dose Dose*Condition Pathology Histopathology Toxicity Bioavailability ToxicityExample 6F 20 20 mg/m² × 5 mg No change No change No change No changeLow-moderate Respiratory Doxorubicin mg/m² 1 (absorption tract toxicityFeasibility 40 mg/m² × 10 mg × 3 Mild- ↑ WBC Airway rate limited) 3doses doses moderate Thoracic & GI epithelial (120 pulmonary Lymphoiddegenera- mg/m² edema depletion tion total) ↑↑ IRR 120 mg/m² × 30 mg × 3Marked ↑↑ WBC Thoracic & GI Moderate- 3 doses doses edema Lymphoidsevere (360 ↑↑ IRR depletion inflamma- mg/m² tion total) Example 6R N/A24-36 12-18 mg ↑ IRR ↓ WBC Mild-moderate Mild- Low-moderate RespiratoryDoxorubicin mg/m² per dose Mild thoracic and moderate tract toxicityDose Range- (5 wkly Rx) transient mesenteric degenera- Finding pulmonarylymphoid tion of edema depletion airway epithelium Mild- moderateinterstitial inflam.

[0138] Plasma levels of doxorubicin were dose dependent and exhibitedclear evidence of drug accumulation, including daily increases in Cmax(maximum concentration in blood) and steady state-like profiles,suggesting there was a rate limited absorption from the lung into theblood with significant accumulation of doxorubicin in the lungsfollowing each additional exposure given at a frequency of dailyintervals. This accumulation was considered likely responsible for thetissue damage observed.

[0139] Referring again to Tables 7 and 9, an inhalation dose range of20-40 mg/m² was administered in five weekly doses that resulted in abody exposure of about 10 mg to about 20 mg, a pulmonary deposited doserange of about 10 to about 20 mg or a range of about 0.25 mg/m² to about0.5 mg/m² lung surface area. The clinical condition included increasedrespiratory rate and mild transient pulmonary edema. A decrease in whiteblood cell count was noted for the higher dosages. Histopathologyrevealed mild to moderate thoracic and mesenteric lymphoid depletion.Respiratory tract toxicity noted was mild to moderate degeneration ofairway epithelium. A mild to moderate to marked interstitialinflammation was noted with some limited fibrosis. Bioavailability wasnoted to be low to moderate with absorption being rate limited. Theprobable dose limiting toxicity appears again to be respiratory tracttoxicity.

EXAMPLE 7F and 7R

[0140] Referring now to Table 10, 1.4 mg of vincristine was initiallyadministered by IV. After the washout period one inhalation feasibilitytest was made. The vincristine was formulated in a 50% water/50% ethanolvehicle. A single dose of 2.8 mg/m² of vincristine was administered thatgave about a 1.8 mg body dose, a pulmonary deposited dose of about 0.9mg or about 2.25 mg/m² lung surface area. No changes were noted in theanimal from this dose. TABLE 10 Vincristine & Vinorelbine SummaryResults of Dog Feasibility and Dose Range-Finding Studies ProbablePulmonary Respiratory Dose- IV Inhalation Deposited Clinical ClinicalTract Limiting Chemotherapy dose Dose Dose Condition PathologyHistopathology Toxicity Bioavailability Toxicity Example 7F 1.4 2.8mg/m² × 0.7 mg Normal Normal No change No change Undetermined Undeter-Vincristine mg/m² 1 mined Feasibility Example 7R N/A 1.1-3.0 0.55-1.5Normal ↓ WBC Minimal-mild Minimal Undetermined Myelosuppr Vincristinemg/m² (6 mg/dose bone marrow interstitial ession Dose Range- wkly Rx)and lymphoid inflammati Finding depletion on Example 7R N/A 12-30 6-15mg Normal ↓ WBC Bone marrow Minimal Undetermined Myelo- Vinorelbinemg/m² (5 per dose and lymphoid pulmonary suppressio Dose Range- wkly Rx)depletion and airway n Finding inflam.

[0141] Referring now to Tables 7 and 10, range finding tests of inhaledvincristine were made in the range of 0.5 to 1.5 mg of pulmonarydeposited vincristine administered in six weekly doses. Therefore theamount of pulmonary deposited dose ranged from about 12.5-37.5 μg/m²lung surface area. This corresponded to a total body dose of 50-150μg/kg or 1.0-3.0 mg/m² of body surface area. This dose range is near andgenerally above typical dose ranges for vincristine given IV. But in theexamples given here, the entire dose was administered to the lungs.Vincristine is a potent drug and causes significant myelosuppression andneurotoxicity at doses above 1.0 mg/m² given systemically. The resultsof the pilot inhalation studies showed the drug was well tolerated atall doses delivered by pulmonary administration with little to noevidence of respiratory tract toxicity with mild lymphoiddepletion/myelosuppression only occurring at the highest doses given(2.0-3.0 mg/m²).

EXAMPLE 8R

[0142] Vinorelbine, which is also a vinca alkaloid was evaluated in arepeated exposure pilot tests. Compared to vincristine, vinorelbine wasapproximately 5-10 times less potent in producing toxicity, but producedsimilar types of changes. Vinorelbine delivered by pulmonaryadministration directly into the lungs of dogs by endotracheal tube, ona weekly basis (for 5 weeks) at escalating doses was well tolerated. Adose of 6 mg deposited in the lung was initially selected and escalatedto 15 mg deposited within the lung. This represented a lung surfaceexposure of ˜0.15-0.375 mg/m² of lung surface area and total body dosesof 12-30 mg/m². This treatment regimen produced very minimal effectswithin the respiratory tract, characterized principally by slightinflammation. At the higher dose levels, inhaled vinorelbine producedsufficient blood levels to cause mild to moderate myelosuppression andlymphoid depletion, both of which were reversible and of a severity,which was not life-threatening.

EXAMPLES 9F and 9R

[0143] An additional proof of concept, pilot inhalation tests involvedetoposide. Etoposide is a cytotoxic drug, representative of a class ofdrugs known as topoisomerase II inhibitors. Given orally or IV,etoposide causes typical cytotoxic systemic toxicity, includingmyelosuppression, severe GI toxicity and alopecia. Etoposide is a highlyinsoluble drug and therefore difficult to formulate. The vehicle usedclinically also causes adverse effects, predominantly anaphylactic typereactions.

[0144] In this invention, etoposide was reformulated in a novel vehicle,dimethylacetamide (DMA) which does not cause anaphylactic reactions.While DMA cannot be used for IV administration due to systemic toxicity,it was shown to be a safe delivery vehicle for the pulmonary route ofdelivery. The etoposide was delivered in a 100% DMA vehicle. Thisformulation allowed the formation of the appropriate particle sizes. Inthese tests, escalating doses of etoposide were given to dogs on aweekly schedule. The initial dose used was 25 mg of etoposide depositedin the pulmonary region with a e and final dose delivered of 80 mgdeposited within the pulmonary region. This equated to a dose range of50-160 mg/m² of body surface area. This treatment regimen caused nosystemic toxicity and only minimal inflammation of the lung and no overtdamage of the respiratory tract. In addition, there was good evidence oflymphoid depletion of the thoracic lymph nodes, in the absence ofsystemic changes, indicating that the drug was draining directly throughthe regional lymph system. This would provide additional regionaltherapeutic effectiveness in dealing with metastatic cells.

[0145] An additional pharmacokinetic test of inhaled etoposide showedthe drug had moderately good bioavailability. A single inhaled totaldeposited dose of 260 mg/m² (about 65 mg of drug deposited in thepulmonary region) produced blood levels of etoposide similar to an IVdose of 50 mg/m² (see FIGS. 1-3). In other words, to reach similar bloodconcentrations approximately 5× more drug was given by inhalation, adose which caused neither respiratory tract nor systemic toxicity.

EXAMPLE 10F

[0146] Additional proof of concept inhalation studies involved thecytotoxic drug 9-aminocamptothecin (9-AC) which is within the drug classknown as camptothecins. Like etoposide, 9-AC is insoluble and difficultto formulate. Supporting the concept and claims of this invention, theinventors generated aerosols of 9-AC formulated as a microsuspension inan aqueous vehicle (100% water).

[0147] These aerosols were delivered to dogs at daily doses of 40 mg/m²body surface area (10 mg of drug deposited within the pulmonary region)for 3 consecutive days. Inhalation treatment produced lower drug plasmalevels than an IV dose of 10 mg/m². The daily inhalation dose was 4times greater than the IV dose and the total cumulative 3 day inhalationdose was 12 times greater than the single IV dose given (which causesmild systemic toxicity). Despite the significantly greater doses givenby inhalation, there were no measurable toxic effects (neither localeffects within the respiratory tract nor systemic changes). Results fromthese tests supported the concept of improved overall safety anddose-intensification within the respiratory tract and also demonstratedthe concept with aerosolized microsuspensions of chemotherapeutic drugs.

EXAMPLE 11F

[0148] In addition, this feasibility trial was extended to examineanother platinum-containing chemotherapeutic, carboplatin. The usualclinical formulation using water was used. Carboplatin is generallyconsidered less toxic than cisplatin at comparable doses, and thisappeared consistent with the results seen when the two agents weredelivered by inhalation. Inhaled doses of up to 30 mg carboplatindeposited via endotracheal tube into the lungs of dogs (60 mg/m² totalbody dose) caused no evidence of either direct respiratory tract orsystemic toxicity. TABLE 11 Etoposide, & 9-Aminocampothecin (9-AC)Summary Results of Dog Feasibility and Dose Range-Finding StudiesProbable Pulmonary Respiratory Dose- Inhalation Deposited ClinicalClinical Tract Limiting Chemotherapy IV dose Dose Dose* ConditionPathology Histopathology Toxicity Bioavailability Toxicity Example 9F 50260 mg/m² × 65 mg × 3 Normal No change Mild thoracic None ModerateUndeter- Etoposide mg/m² 3 (780 doses lymphoid mined Feasibility mg/m²depletion total dose) Example 9R N/A 50-160 25-80 mg Normal No changeMild-moderate Mild Moderate Undeter- Etoposide Dose mg/m² (6 dosethoracic interstitial mined Range-Finding wkly Rx) lymphoid inflamma-depletion tion Example 10F 10 40 mg/m² × 10 mg × 3 Normal No changeMinimal Minimal Moderate-high Undeter- 9-AC Feasibility mg/m² 3 (120doses lymphoid interstitial mined mg/m² depletion inflamma- total) tion

EXAMPLES 12 to 20

[0149] These examples illustrate results of clinical treatment of dogshaving end stage lung cancer where other treatments have failed. Fortreatment, the dogs were anaesthetized and the inhalation treatment wasthrough an endotracheal tube.

[0150] This preliminary trial was performed to determine whether theinhalation chemotherapy treatment could be successfully used in animalswith lung tumors. Initially, nine dogs with neoplastic lung disease werestudied. Three different drugs were used—doxorubicin, vincristine,cyclophosphamide, cisplatin, and paclitaxel at the doses and schedulessummarized in Table 12.

[0151] One 16 year old mixed breed dog had no evidence of tumor in thelung following excision of a primary lung tumor, but did have evidenceof metastases in the hilar lymph nodes, a sign that metastases wouldsoon appear in the lung. However, the results showed that no metastasesdeveloped in the lung for four months during which time the dog receivedfour treatments of inhaled doxorubicin. In six other dogs, there weremetastases in the lung and in each of these, the inhaled chemotherapystopped the growth of the metastases, i.e. there was stable disease (orSD). In two dogs inhalational chemotherapy was not effective and therewas progressive disease (or PD). Since no chemotherapy was given tothese dogs by the intravenous route, tumors outside of the lungprogressed even while the lung tumors were stabilized. Thus, the resultsdemonstrated that inhalational chemotherapy was effective in the localtreatment of lung cancer in the dog. TABLE 12 Summary of PreliminaryClinical Results in Dogs Time of Ex. Dog Type and Age DiagnosisInhalation Treatment* Trial Results 12 Afghan Advanced lung carcinomaDox 5 mg, ×1 1 week PD extrapulmonary 10 years old 13 Cocker SpanielLung metastasis from Dox 5 mg, ×2 2 mo. SD lung, died 10-12 years oldexcised melanoma Vincristine 0.5 mg, once PD extrapulmonary, died 14Beagle Thyroid carcinoma with Dox 5 mg, ×4 4 mo. SD lung 7 years oldlung metastasis PD thyroid & extrapulmonary, died 15 Labrador Thyroidcarcinoma with Dox 5 mg, ×2 2 mo. SD lung 8 years old lung metastasis PDthyroid & brain metastasis, died 16 Mixed Breed Excised lung primary,Dox 5 mg, ×4 4 mo. No lung metastasis 16 years old positive hilar lymphnodes Death CNS metastasis 17 Rottweiler Excised distal Dox 7 mg, ×2 1mo. PD lung 3 years old osteosarcoma, lung Cisplatin 15 mg, ×1 FurtherRx declined nodule 18 Mixed Breed Lung metastasis (Dox 5 mg + CTX 252-{fraction (1/2 )}mo. SD lung 14 years old (carcinoma) mg)1 ×3 PDvisceral & Extrapulmonary, died Dox 5 mg, ×1 19 Flat-coated RetrieverExcised salivary adeno- Paclitaxel 22.5 mg, QW × 2-{fraction (1/2 )}mo.SD (4 weeks) lung 8 years old carcinoma, lung 4 PD lung, Rx discontinuedmetastasis 20 Husky Advanced mammary Paclitaxel 22.5 mg, ×2 2 mo. SDlung 16 years old adenocarcinoma, lung (Paclitaxel 22.5 mg + metastasisDox 5 mg), ×2

EXAMPLES 21 to 33

[0152] Additionally, tests were conducted in dogs using a definedprotocol. In these tests, dogs with either gross metastatic disease,micrometastatic hemangiosarcoma or micrometastatic primary lung cancerwere randomized to receive either doxorubicin, paclitaxel or both byinhalation via an endotracheal tube in a crossover design. Aerosolparticle size was 2-3 μm as in the previous tests. The apparatus usedwas basically that shown in FIG. 5 and as described above. Formulationsfor administration of the drugs were as follows: 16 mg/ml doxorubicin in70% ethanol/30% water; 75 mg paclitaxel in about 30% PEG/70% ethanol.Preferably the paclitaxel is administered with 0.2% of citric acid toprevent degradation of the drug unless it is immediately used afterpreparation. The treatments were administered once every two weeks, andif a diagnosis of progressive disease was made on two consecutiveintervals the dog was crossed over to the alternate drug. At eachtreatment session, blood was sampled for hematology and biochemicalanalyses and urine was collected for analysis. The status of the tumorswas monitored radiographically.

[0153] The results are summarized in Table 13. Pulmonary deposited doseslisted in the table are based on scintigraphy studies that relateinhaled doses to deposited doses. Among the 10 dogs that had grossmetastatic disease (Examples 21-28), which is regarded as a terminalcondition with a very short life expectancy, 4 dogs (in Examples 21, 22,24, and 27) showed stable disease in the lung indicating that the drugwas having a positive effect. In the remaining 6 dogs (see Examples 23,25, 26, and 28), the lung disease progressed. In two of the dogs withmetastatic osteosarcoma (Examples 24 and 25) and in the dog withmetastatic melanoma (Example 28), there were partial responses, i.e.there were tumors that decreased in size by more than 50%.

[0154] Four dogs had splenic hemangiosarcoma (Examples 29 and 30), adisease that invariably metastasizes to the lung and is fatal within twoto four months. These dogs were given doxorubicin by inhalation inaddition to intravenous chemotherapy to control systemic disease. Theresults in Table 13 show that each of the four dogs was alive (at leasttwo months at the time of this writing) and that there was no evidenceof disease in the lung.

[0155] The last group of dogs (Examples 31-33) are those that hadprimary lung tumors which were removed surgically. These dogs hadmetastases in their thoracic lymph nodes and have a life expectancymeasured in weeks. As shown in Table 13, two dogs (Examples 31 and 32)received doxorubicin by inhalation (1.5 mg) and two dogs (Example 33)received paclitaxel (20 mg). The dog that received five treatments ofdoxorubicin was alive with no evidence of disease 81 days latersuggesting that the treatment is having a positive effect. One dog(Example 32) received two doses of doxorubicin and died from metastasesoutside of the lung. The other two dogs (Example 33) have no evidence ofdisease but not enough time has passed to determine how effective thetreatment will be.

[0156] The result of these tests, therefore, confirm those of thepreliminary tests that inhalational chemotherapy is effective in thetreatment of lung cancer. TABLE 13 Efficacy of Inhalational Chemotherapyin Dogs with Lung Cancer No. of Inhalation Ex. Diagnosis Dogs Treatment*Results 21 Lung carcinoma 1 DOX 5 mg (5×) then SD paclitaxel 60 mg (2×)22 Metastatic 1 DOX 5 mg (2×) SD 23 hemangiosarcoma 1 DOX 5 mg (1×) PD24 Metastatic 1 DOX 5 mg (5×) + SD (PR after 3^(rd) DOX osteosarcomapaclitaxel 60 mg (2×) treatment) 25 Metastatic 3 DOX 5mg (2x) + PD (PRin one dog) osteosarcoma paclitaxel 60 mg (1×) 26 Metastatic 1 DOX 5 mg(2×) PD fibrosarcoma 27 Metastatic 1 DOX 5 mg (4×) + SD liposarcomapaclitaxel 60 mg (1×) 28 Metastatic 1 paclitaxel 60 mg (2×) + PD (PRnoted in nodules melanoma DOX 5 mg (1×) <2 cm) 29 Splenic 2 DOX 5 mg(4×) + Alive and NED hemangiosarcoma systemic chemotherapy 30 Splenic 2DOX 1.5 mg(3×) + Alive and NED hemangiosarcoma systemic chemotherapy 31Primary lung 1 DOX 1.5 mg (5×) Alive and NED tumor 32 excised- 1 DOX 1.5mg (2×) Dead from extrapleural micrometastatic metastases 33 disease 2paclitaxel 20 mg (1×) Alive and NED

[0157] The safe and effective range of doses of the inhalantantineoplastic drugs in humans and animals (e.g. dogs and similar smallanimals) are shown in Table 14 below. Larger animal dosages can becalculated by using multiples of the small animal based dose based onthe known relationship of (body weight in kg/m² of body surface area.The exact doses will vary depending upon such factors as the type andlocation of the tumor, the age and size of the patient, the physicalcondition of the patient and concomitant therapies that the patient mayrequire. The dosages shown are for doses for one course of therapy. Acourse of therapy may be given, monthly, weekly, biweekly, triweekly ordaily depending on the drug, patient, type of disease, stage of thedisease and so on. Exemplary safe and effective amounts of carrier aregiven for each product have been published by the respectivemanufacturer and are summarized in the Physicians Desk Reference. TABLE14 Animal Dose* Human Drug mg/m² Dose* mg/m² Doxorubicin 2 to 90 3 to130 Paclitaxel 6 to 270 10 to 400 Vincristine 0.06 to 2 0.1 to 3Vinorelbine 1.3 to 60 2 to 90 Cisplatin 4.6 to 200 7 to 300 Etoposide4.6 to 200 7 to 300 9-Aminocampothecin 2.6 to 10 0.04 to 15

[0158] Based on the results of the inhalation tests herein withdoxorubicin, inhalation treatments with anthracyclines in addition todoxorubicin are also expected to be well tolerated and efficacious whenadministered by the pulmonary route. Based on the inhalation testsherein with vincristine and vinorelbine, other vinca alkaloids areexpected to be well tolerated and efficacious when administered by thepulmonary route. Based on the inhalation tests herein for the vesicantsdoxorubicin, vincristine, vinorelbine, and paclitaxel, all of which arecapable of serious vesicating injuries, other vesicating drugs (e.g.mechlorethamine, dactinomycin, mithramycin, bisantrene, amsacrine,epirubicin, daunorubicin, idarubicin, vinblastine, vindesine, and so on)are expected to be well tolerated and efficacious when administered bythe pulmonary route. The exception, of course, would be vesicant drugsthat are known to exhibit significant pulmonary toxicity whenadministered by IV (e.g. mitomycin-C). In this regard, a safe andeffective amount of a particular drug or agent is that amount whichbased on its potency and toxicity, provides the appropriateefficacy/risk balance when administered via pulmonary means in thetreatment of neoplasms. Similarly a safe and effective amount of avehicle or carrier is that amount based on its solubilitycharacteristics, stability, and aerosol forming characteristics, thatprovides the required amount of a drug to the appropriate site in thepulmonary system for treatment of the neoplasm.

[0159] For the nonvesicant antineoplastic drugs, based on the inhalationtests herein for the vesicating and nonvesicating drugs it is expectedthat all the nonvesicating drugs that do not exhibit direct pulmonarytoxicity when administered intravenously are expected be well toleratedand exhibit efficacy. Bleomycin and mitomycin-C, for example, exhibitsufficient pulmonary toxicity to be excluded except when achemoprotectant is used. In this regard typically carmustine,dacarbazine, melphalan, methotrexate, mercaptopurine, mitoxantrone,esorubicin, teniposide, aclacinomycin, plicamycin, streptozocin,menogaril are expected to be well tolerated and exhibit efficacy.Similarly, drugs of presently unknown classification such asgeldanamycin, bryostatin, suramin, carboxyamido-triazoles such as thosein U.S. Pat. No. 5,565,478, onconase, and SU101 and its activemetabolite SU20 are likewise expected to be well tolerated and exhibitefficacy subject to the limitation on pulmonary toxicity. These drugswould be administered by the same methods disclosed for the testedantineoplastic drugs. They would be formulated with a safe and effectiveamount of a vehicle and administered in amounts and in a dosing schedulesafe and effective for treating the neoplastic disease.

[0160] Pulmonary toxicity of compounds to be administered by inhalationis an important consideration. As mentioned above one of the majorconsiderations is whether the drug exhibits significant pulmonarytoxicity when injected by IV. While almost all antineoplastic drugs aretoxic to the body and thus arguably exhibit pulmonary toxicity if givenin a large enough dose, the test for pulmonary toxicity as used hereinrequires significant pulmonary toxicity at the highest manufacturersrecommended dose that is to be administered to a patient. Thedetermination of whether a drug exhibits sufficient pulmonary toxicityby IV so as to exclude it from the group of drugs useful for pulmonaryadministration can be made from the drug manufacturers recommendationsas published in the Physicians Desk Reference (see “Physicians DeskReference” 1997, (Medical Economics Co.), or later editions thereof), inother drug manuals published for health care providers, publiclyavailable filings of the manufacturer with the FDA, or in literaturedistributed directly by the manufacturers to physicians, hospitals, andthe like. For example in the “Physicians Desk Manual” 1997:

[0161] Doxorubicin (Astra) pp. 531-533—vesicant, there is no indicationof pulmonary toxicity while cardiac toxicity, hematologic toxicityparticularly leukopenia and myelosuppression; extravasation injuries arealso noted;

[0162] Idarubicin (Pharmacia & Upjohn) pp 2096-2099—vesicant, primarytoxicity appears to be myelosuppression no mention is made of pulmonarytoxicity making the drug useful in the present invention;

[0163] Etoposide (Astra) pp539-541—no indication of pulmonary toxicity,but dose limiting hematologic toxicity is important;

[0164] Paclitaxel (Bristol-Meyers Squibb) pp. 723-727—vesicant,pulmonary toxicity is not listed for paclitaxel, but dose limiting bonemarrow suppression (primarily neutropenia) is important;

[0165] Bleomycin (Blenoxane® Bristol-Meyers Squibb) pp. 697-699,pulmonary toxicities occur in about 10% of treated patients by IVadministered drug, this makes bleomycin unacceptable for pulmonaryadministration for the present invention;

[0166] Mitomycin C (Mutamycin® Bristol-Meyers Squibb)—vesicant,infrequent but severe life threatening pulmonary toxicity has occurredby IV administration, this although infrequent severe life threateningpulmonary toxicity shows that the drug exhibits substantial pulmonarytoxicity;

[0167] Methotrexate (Immunex) pp. 1322-1327—MW=454, primary toxicityappears to be hepatic and hematologic, signs of pulmonary toxicityshould be closely monitored for signs of lesions;

[0168] Dactinomycin (Merck & Co.)—vesicant, primary toxicity appears tobe oral, gastrointestinal, hematologic, and dermologic; no mention ismade of pulmonary toxicity making the drug acceptable in the presentinvention;

[0169] mechlorethamine (Merck & Co.)—vesicant, primary toxicity appearsto be renal, hepatic and bone marrow, no mention is made of pulmonarytoxicity making the drug acceptable in the present invention;

[0170] Irinotecan (Camptosar® Pharmacia & Upjohn)—a derivative ofcamptothecin, primary toxicity appears to be severe diarrhea andneutropenia, no mention is made of pulmonary toxicity making the druguseful in the present invention;

[0171] Vincristine (Oncovin® Lilly) pp. 1521-1523—extremely toxic withhigh vesicant activity found in the tests herein, but no pulmonarytoxicity noted;

[0172] Vinblastine (Velban® Lilly) pp.1537-1540—extremely toxic withhigh vesicant activity found in the tests herein, but no pulmonarytoxicity noted.

[0173] The above listing is exemplary only and is not intended to limitthe scope of the invention.

[0174] An additional embodiment of the invention includes methods andformulations that contain chemoprotectants and are administered byinhalation for preventing toxicity and particularly pulmonary toxicitythat may be elicited by antineoplastic drugs. The method would allow theuse by inhalation of antineoplastic drugs that exhibit pulmonarytoxicity or would reduce the likelihood of pulmonary toxicity. Onemethod would include treating a patient having a neoplasm, viainhalation administration, a pharmaceutically effective amount of ahighly toxic antineoplastic drug and a pharmaceutically effective amountof a chemoprotectant, wherein the chemoprotectant reduces or eliminatestoxic effects in the patient that are a result of inhaling the highlytoxic antineoplastic drug. More narrowly, another embodiment includes acombination of inhaled chemoprotectant and antineoplastic drug thatreduces or eliminates respiratory tract or pulmonary tract toxicity inthe patient. The chemoprotectant can be coadministered with theantineoplastic drug by inhalation, or both by inhalation and by IV, orthe chemoprotectant can be administered alone.

[0175] It is known, for example, that dexrazoxane (ICRF-187) when givenby intraperitoneal injection to mice is protective against pulmonarydamage induced by bleomycin given by subcutaneous injections. See forexample Herman, Eugene et al, “Morphologic and morphometric evaluationof the effect of ICRF-187 on bleomycin-induced pulmonary toxicity”,Toxicology 98, (1995) pp. 163-175, the text of which is incorporated byreference as if fully rewritten herein. The mice pretreated withintraperitoneal injections of dexrazoxane prior to having bleomycininjected subcutaneously showed reduced pulmonary alterationsparticularly fibrosis compared to another group of mice that was notpretreated. The following examples illustrate the use of achemoprotectant by inhalation in conjunction with an antineoplasticdrug.

EXAMPLE 34

[0176] Dexrazoxane (ICRF-187) is dissolved in a pharmaceuticallyacceptable liquid formulation and administered to a patient as anaerosol using the apparatus and methods described herein, at a doseranging from 10 mg to 1000 mg over a period of from one minute to oneday prior to giving a chemotherapeutic drug such as doxorubicin byinhalation. The doxorubicin is given in a dose from 1 mg to 50 mg.

EXAMPLE 35

[0177] Dexrazoxane (ICRF-187) is administered as described in Example 34at the same time or up to two hours before giving bleomycin byintravenous injection. The dose of dexrazoxane ranges form about 2 timesto about 30 times the dose of bleomycin. The dose of bleomycin by IVranges from about 5 to 40 units/m².

EXAMPLE 36

[0178] Dexrazoxane (ICRF-187) is administered as described in Example 34at the same time or up to two hours before administering bleomycin byinhalation. The dose of dexrazoxane ranges from about 2 times to about30 times the dose of bleomycin. The dose of bleomycin by inhalationranges from 5 to 40 units/m² at intervals of from 1 week to 4 weeks.

EXAMPLES 37 and 38

[0179] Chemoprotectants such as mesna (ORG-2766), and ethiofos (WR2721)may be used in a manner similar to that described in Examples 34 to 36,above.

[0180] Combination Therapy

[0181] Another embodiment of the invention contemplates drugcoadministration by the pulmonary route, and by (1) other local routes,and/or (2) systemically by IV. Results from the clinical tests on dogsindicates that, although the pulmonary route of administration willindeed control neoplastic cells arising in or metastatic to thepulmonary tract, neoplastic cells elsewhere in the body may continue toproliferate. This embodiment provides for effective doses of drug in thelung delivered via the lung and additional drug delivered via (1) otherlocal sites (e.g. liver tumors may also be treated via hepatic arteryinstillation, ovarian cancer by intraperitoneal administration) and/oradditional drug(s) may be provided systemically by IV via the generalcirculatory system. Administration can be at the same time, oradministration followed closely in time by one or more of the othertherapeutic routes. Benefits are that much higher dosages can besupplied to affected tissues and effective control of neoplasms can bemaintained at multiple critical sites compared to using a single mode ofadministration.

[0182] Also contemplated within the scope of the invention is thecombination of drugs for combination chemotherapy treatment. Benefitsare those well known in the treatment of cancer using combinationchemotherapy by other routes of administration. For example, combiningdrugs with different mechanisms of action such as an alkylating agentplus a mitotic poison plus a topoisomerase inhibitor. Such combinationsincrease the likelihood of destroying tumors that are comprised of cellswith many different drug sensitivities. For example, some are easilykilled by alkylating agents while mitotic poisons kill others moreeasily.

[0183] Also included in the invention are embodiments comprising themethod for inhalation therapy disclosed herein and the application ofradiotherapy, gene therapy, and/or immunotherapy. Other embodimentsinclude the immediately above method combined with chemotherapy appliedby IV and/or local therapy.

[0184] Also included within the invention are formulations forpaclitaxel. In these formulations 100% to 40% ethanol is useful.However, to obtain better control of particle size and stable aerosolgeneration the addition of polyethylene glycol (PEG) is preferred.Although 1-60% PEG can be used about 8-40% PEG is more preferred, and10-30% PEG was found to be optimal. A further embodiment also includesthe addition of 0.01 to 2% of an organic or inorganic acid, preferablyan organic acid such as citric acid and the like. The acid being addedto stabilize the formulation. With regard to clinical use in inhalation,citric acid in water has been found to cause tussive andbronchioconstrictive effects. PEG may ameliorate this effect. Theformulation contains a safe and effective amount of paclitaxel usefulfor the treatment of neoplasms.

[0185] While the forms of the invention herein disclosed constitutepresently preferred embodiments, many others are possible. It is notintended herein to mention all of the possible equivalent forms orramifications of the invention. It is to be understood that the termsused herein are merely descriptive, rather than limiting, and thatvarious changes may be made without departing from the spirit of thescope of the invention.

We claim:
 1. A formulation for treating a patient for a neoplasm byinhalation comprising: an effective amount of a vesicant and apharmaceutically acceptable carrier, wherein said vesicant does notexhibit substantial pulmonary toxicity.
 2. The formulation according toclaim 1 , wherein said vesicant comprises a moderate vesicant.
 3. Theformulation according to claim 1 , wherein said vesicant comprisespaclitaxel and carboplatin.
 4. The formulation according to claim 1 ,wherein said moderate vesicant comprises: a non-encapsulated anticancerdrug, wherein when 0.2 ml of said drug is injected intradermally torats, at the clinical concentration for parenteral use in humans: (a) alesion results that is at least 20 mm² in area fourteen days after saidintradermal injection; and (b) at least 50% of the tested rats have thissize of lesion.
 5. The formulation according to claim 1 , wherein saidvesicant comprises a severe vesicant.
 6. The formulation according toclaim 1 , wherein said vesicant comprises a severe vesicant selectedfrom the group comprising doxorubicin, vincristine, and vinorelbine. 7.The formulation according to claim 1 , wherein said neoplasm is apulmonary neoplasm, a neoplasm of the head and neck, or other systemicneoplasm.
 8. The formulation according to claim 1 , wherein said drug isin the form of a liquid, a powder, a liquid aerosol, or a powderedaerosol.
 9. The formulation according to claim 1 , wherein said drugcomprises tubulin inhibitors.
 10. The formulation according to claim 1 ,wherein said drug comprises alkylating agents.
 11. The formulationaccording to claim 1 , wherein said drug comprises an anthracycline. 12.The formulation according to claim 11 , wherein said anthracycline isselected from the group consisting of epirubicin, daunorubicin,methoxymorpholinodoxorubicin, cyanomorpholinyl doxorubicin, doxorubicin,and idarubicin.
 13. The formulation according to claim 12 , wherein whendoxorubicin is selected said effective amount of said drug for animalsis about 2 to 90 mg/m² and the human dose is about 3 to 130 mg/m²,wherein both doses are based on body surface area.
 14. The formulationaccording to claim 1 , wherein said drug is a vinca alkaloid.
 15. Theformulation according to claim 14 , wherein said vinca alkaloid isselected from the group consisting of vincristine, vinorelbine,vinorelbine, vindesine, and vinblastine.
 16. The formulation accordingto claim 15 , wherein when vincristine is selected the animal dose isabout 0.06 to 2 mg/m² and the human dose is about 0.1 to 3 mg/m²; andwhen vinorelbine is selected animal dose is about 1.3 to about 60 mg/m²and the human dose is about 2 to 90 mg/m², wherein all doses are basedon body surface area.
 17. The formulation according to claim 1 , whereinsaid drug is a vesicant selected from the group consisting ofmechlorethamine, mithramycin, and dactinomycin.
 18. The formulationaccording to claim 1 , wherein said drug is bisantrene.
 19. Theformulation according to claim 1 , wherein said drug is amsacrine. 20.The formulation according to claim 1 , wherein said drug is a taxane.21. The formulation according to claim 1 , wherein said drug ispaclitaxel.
 22. The formulation according to claim 21 , wherein theanimal dose is 6 to 90 mg/m², and the human dose is 10 to 400 mg/m²wherein both doses are based on body surface area.
 23. A formulation fortreating a patient having a neoplasm by inhalation comprising: (1) asafe and effective amount of a non-encapsulated antineoplastic drughaving a molecular weight above 350, that does not exhibit substantialpulmonary toxicity; and (2) an effective amount of a pharmaceuticallyacceptable carrier.
 24. The formulation according to claim 23 , whereinsaid neoplasm is a pulmonary neoplasm, a neoplasm of the head and neck,or a systemic neoplasm.
 25. The formulation according to claim 23 ,wherein said drug is in the form of a liquid, a powder, a liquidaerosol, or a powdered aerosol.
 26. The formulation according to claim23 , wherein said drug has a protein binding affinity of 25% or more.27. The formulation according to claim 26 , wherein said drug has aprotein binding affinity of 50% or more.
 28. The formulation accordingto claim 23 , wherein said drug has a molecular weight above
 400. 29. Aformulation for treating a patient for a neoplasm by inhalationcomprising: a safe and effective amount of a taxane in an effectiveamount of vehicle comprising polyethyleneglycol (PEG) and an alcohol.30. The formulation according to claim 29 , further comprising an acid,said acid present in amount effective to stabilize said taxane.
 31. Theformulation according to claim 29 , wherein said alcohol is ethanol. 32.The formulation according to claim 29 , wherein said acid is an organicacid.
 33. The formulation according to claim 29 , wherein said acid iscitric acid.
 34. The formulation according to claim 29 , wherein saidtaxane comprises paclitaxel.
 35. The formulation according to claim 34 ,comprising about 8% to 40% polyethyleneglycol, about 90% to 60% alcohol,and about 0.01% to 2% acid.
 36. The formulation according to claim 35wherein said safe and effective amount provides an animal dose of about6 to about 90 mg/m² and a human dose of about 10 to 400 mg/m², whereinsaid dose is based on body surface area.
 37. A formulation for treatinga patient for a neoplasm by inhalation comprising: a safe and effectiveamount of a drug selected from the group consisting of carmustine,dacarbazine, melphalan, mercaptopurine, mitoxantrone, esorubicin,teniposide, aclacinomycin, plicamycin, streptozocin, and menogaril; anda safe and effective amount of a pharmaceutically effective carrier,wherein said drugs do not exhibit substantial pulmonary toxicity.
 38. Aformulation for treating a patient for a neoplasm by inhalationcomprising: a safe and effective amount of a drug selected from thegroup consisting of estramustine phosphate, geldanamycin, bryostatin,suramin, carboxyamido-triazoles; onconase, and SU101 and its activemetabolite SU20; and a safe and effective amount of a pharmaceuticallyeffective carrier, wherein said drugs do not exhibit substantialpulmonary toxicity.
 39. A formulation for treating a patient for aneoplasm by inhalation comprising: a safe and effective amount ofetoposide and a DMA carrier.
 40. The formulation according to claim 39 ,wherein said formulation provides an animal dose of about 4.6 to 200mg/m² and a human dose of about 7 to 300 mg/m^(2,) wherein said dosesare base on body surface area.
 41. A formulation for treating a patientfor a neoplasm by inhalation comprising: a safe and effective amount ofa microsuspension of 9-aminocamptothecin in an aqueous carrier.
 42. Theformulation according to claim 39 , wherein said formulation provides ananimal dose of about 2.6 to 10 mg/m² and a human dose of about 0.04 to15 mg/m², wherein said doses are base on body surface area.
 43. Aformulation for treating a patient having a neoplasm comprising:administering to said patient by inhalation, (1) an effective amount ofa highly toxic antineoplastic drug; and (2) an effective amount of achemoprotectant, wherein said chemoprotectant reduces or eliminatestoxic effects in said patient that are a result of administering saidhighly toxic antineoplastic drug.
 44. The formulation according to claim43 , wherein said chemoprotectant reduces or eliminates systemictoxicity in said patient.
 45. The formulation according to claim 43 ,wherein said chemoprotectant reduces or eliminates respiratory tracttoxicity in said patient.
 46. The formulation according to claim 43 ,wherein said chemoprotectant comprises dexrazoxane (ICRF-187), mesna(ORG-2766), ethiofos (WR2721), or a mixture thereof.
 47. The formulationaccording to claim 43 , wherein said chemoprotectant is administeredbefore, after, or during said administration of said antineoplasticdrug.
 48. The formulation according to claim 431 wherein saidantineoplastic drug comprises a nonvesicant.
 49. The formulationaccording to claim 43 , wherein said antineoplastic drug comprises amoderate vesicant.
 50. The formulation according to claim 43 , whereinsaid antineoplastic drug comprises a severe vesicant.
 51. Theformulation according to claim 43 , wherein said antineoplastic drugcomprises bleomycin.
 52. The formulation according to claim 43 , whereinsaid antineoplastic drug comprises doxorubicin.
 53. The formulationaccording to claim 43 , wherein said antineoplastic drug comprisesmitomycin-C.
 54. A method for treating a patient having a neoplasmcomprising: administering to said patient by inhalation, (1) aneffective amount of a highly toxic antineoplastic drug; and (2) aneffective amount of a chemoprotectant, wherein said chemoprotectantreduces or eliminates toxic effects in said patient that are a result ofadministering said highly toxic antineoplastic drug.
 55. The methodaccording to claim 54 , wherein said chemoprotectant reduces oreliminates systemic toxicity in said patient.
 56. The method accordingto claim 54 , wherein said chemoprotectant reduces or eliminatesrespiratory tract toxicity in said patient.
 57. The method according toclaim 54 , wherein said chemoprotectant comprises dexrazoxane(ICRF-187), mesna (ORG-2766), ethiofos (WR2721), or a mixture thereof.58. The method according to claim 54 , wherein said chemoprotectant isadministered before, after, or during said administration of saidantineoplastic drug.
 59. The method according to claim 54 , wherein saidantineoplastic drug comprises a nonvesicant.
 60. The method according toclaim 54 , wherein said antineoplastic drug comprises a moderatevesicant.
 61. The method according to claim 54 , wherein saidantineoplastic drug comprises a severe vesicant.
 62. The methodaccording to claim 54 , wherein said antineoplastic drug comprisesbleomycin.
 63. The method according to claim 54 , wherein saidantineoplastic drug comprises doxorubicin.
 64. The method according toclaim 54 , wherein said antineoplastic drug comprises mitomycin-C.
 65. Amethod for treating a patient having a neoplasm comprising:administering a pharmaceutically effective amount of a non-encapsulatedantineoplastic drug to said patient by inhalation, said drug selectedfrom the group consisting of antineoplastic drugs wherein when 0.2 ml ofsaid drug is injected intradermally to rats, at the clinicalconcentration for IV use in humans: (a) a lesion results which isgreater than 20 mm² in area fourteen days after said intradermalinjection; and (b) at least 50% of the tested rats have these lesions.66. The method according to claim 65 , wherein when said drug isdoxorubicin or vinblastine sulfate, said drug is inhaled in the absenceof perfluorocarbon.
 67. The method according to claim 65 , wherein saidneoplasm is a pulmonary neoplasm, a neoplasm of the head and neck, orother systemic neoplasm.
 68. The method according to claim 65 , whereinsaid drug is inhaled as a liquid aerosol or as a powdered aerosol. 69.The method according to claim 65 , wherein said patient is a mammal. 70.The method according to claim 65 , wherein said patient is a human. 71.The method according to claim 65 , wherein said drug is an anthracyclineselected from the group consisting of doxorubicin, daunorubicin,methoxymorpholinodoxorubicin, epirubicin, cyanomorpholinyl doxorubicin,and idarubicin.
 72. The method according to claim 65 , wherein said drugis a vinca alkaloid.
 73. The method according to claim 65 , wherein saiddrug is selected from the group consisting of vincristine, vinorelbine,vindesine, and vinblastine.
 74. The method according to claim 65 ,wherein said drug is selected from the group consisting ofmechlorethamine, mithramycin and dactinomycin.
 75. The method accordingto claim 65 , wherein said drug comprises bisantrene.
 76. The methodaccording to claim 65 , wherein said drug comprises amsacrine.
 77. Themethod according to claim 65 , wherein said drug comprises a taxane. 78.The method according to claim 77 , wherein said taxane comprisesdoxitaxel.
 79. The method according to claim 77 , wherein said drugcomprises paclitaxel.
 80. A method for treating a patient having aneoplasm comprising: administering an effective amount of a highly toxicnon-encapsulated antineoplastic drug to a patient by inhalation, whereinthe molecular weight of said drug is above 350, and said drug has nosubstantial pulmonary toxicity.
 81. The method according to claim 80 ,wherein said neoplasm is a pulmonary neoplasm, a neoplasm of the headand neck, or a systemic neoplasm.
 82. The method according to claim 80 ,wherein said drug is inhaled as a liquid aerosol or as a powderedaerosol.
 83. The method according to claim 80 , wherein said drug has aprotein binding affinity of 25% or more.
 84. The method according toclaim 83 , wherein said drug has a protein binding affinity of 50% ormore.
 85. The method according to claim 80 , wherein said drug isselected from the group comprising doxorubicin, epirubicin,daunorubicin, methoxymorpholinodoxorubicin, cyanomorpholinyldoxorubicin, and idarubicin.
 86. The method according to claim 80 ,wherein said drug is a vinca alkaloid administered without the presenceof a perfluorocarbon.
 87. The method according to claim 80 , whereinsaid drug is selected from the group consisting of vincristine,vinorelbine, vindesine, and vinblastine.
 88. The method according toclaim 80 , wherein said drug is mechlorethamine, mithramycin, ordactinomycin.
 89. The method according to claim 80 , wherein said drugis bisantrene or amsacrine.
 90. The method according to claim 80 ,wherein said drug is doxytaxel or paclitaxel.
 91. The method accordingto claim 80 , wherein said patient is a mammal.
 92. The method accordingto claim 80 , wherein said patient is a human.
 93. A method for treatinga patient for a neoplasm comprising: administering an effective amountof an antineoplastic drug to said patient by inhalation; andadministering a pharmaceutically effective amount of the same and/ordifferent antineoplastic drug to said patient parenterally.
 94. Themethod according to claim 93 , wherein said patient also is treated byradiotherapy.
 95. The method according to claim 93 , wherein saidpatient is also treated with immunotherapy.
 96. The method according toclaim 93 , wherein said patient is also treated with gene therapy. 97.The method according to claim 93 , wherein said patient is alsoadministered chemoprotective drugs.
 98. The method according to claim 93wherein said patient is also administered chemopreventive drugs.
 99. Amethod for treating a patient for a neoplasm comprising: administeringan effective amount of an antineoplastic drug to said patient byinhalation; and administering an effective amount of the same and/ordifferent antineoplastic drug to said patient by isolated organperfusion.
 100. The method according to claim 99 , wherein said patientis a mammal.
 101. The method according to claim 99 , wherein saidpatient is a human.
 102. The method according to claim 991 wherein saidpatient is also treated by radiotherapy.
 103. The method according toclaim 991 wherein said patient is also treated by immunotherapy. 104.The method according to claim 99 , wherein said patient is also treatedby gene therapy.
 105. The method according to claim 99 , wherein saidpatient is also administered chemoprotective drugs.
 106. The methodaccording to claim 99 , wherein said patient is also administeredchemopreventive drugs.
 107. A method for treating a patient for apulmonary neoplasm comprising: (1) selecting one or more antineoplasticdrugs efficacious in treating said neoplasm and having a residence timein the pulmonary mucosa sufficient to be efficacious in the treatment ofsaid pulmonary neoplasm; and (2) administering said drug(s) to saidpatient by inhalation in a non-encapsulated form.
 108. The methodaccording to claim 107 , wherein when 0.2 ml of said or at least one ofsaid drugs is injected intradermally to rats, at the clinicalconcentration for parenteral use in humans: A. a lesion results which isgreater than 20 mm in area fourteen days after said intradermalinjection; and B. at least 50% of the tested rats have these lesions.109. The method according to claim 108 , wherein said formulationresults in a lesion which is greater than about 10 mm² in area 30 daysafter said intradermal injection; and at least about 50% of the testedrats have these longer lasting lesions.
 110. The method according toclaim 107 , wherein the molecular weight of at least one of saidselected drugs is above
 350. 111. The method according to claim 107 ,wherein said patient is a mammal.
 112. The method according to claim 107, wherein said patient is a human.
 113. A method of use, comprising theadministration of one or more non-encapsulated highly toxic anticancerdrugs to a mammal by inhalation, wherein at least one of said drugscomprises a severe vesicant.
 114. An apparatus for treating a patientfor a neoplasm by inhalation comprising: in combination a nebulizer anda formulation for treating a neoplasm comprising: (1) a non-encapsulatedanticancer drug, and (2) a pharmaceutically acceptable carrier; whereinwhen 0.2 ml of said formulation is injected intradermally to rats, atthe clinical concentration for parenteral use in humans: (a) a lesionresults which is greater than about 20 mm² in area fourteen days aftersaid intradermal injection; and (b) at least 50% of the tested rats havethese lesions.
 115. The apparatus according to claim 114 , wherein saidformulation results in a lesion which is greater than about 10 mm² inarea 30 days after said intradermal injection; and at least about 50% ofthe tested rats have these longer lasting lesions.
 116. The apparatusaccording to claim 114 , wherein said formulation further comprises ananthracycline.
 117. The apparatus according to claim 116 , wherein saidanthracycline is selected from the group consisting of epirubicin,daunorubicin, methoxymorpholinodoxorubicin, cyanomorpholinyldoxorubicin, doxorubicin, and idarubicin.
 118. The apparatus accordingto claim 114 , wherein said formulation further comprises a vincaalkaloid.
 119. The apparatus according to claim 118 , wherein said vincaalkaloid is selected from the group consisting of vincristine,vinorelbine, vinorelbine, vindesine, and vinblastine.
 120. The apparatusaccording to claim 114 , wherein said formulation comprises a vesicantselected from the group consisting of mechlorethamine, mithramycin, anddactinomycin.
 121. The apparatus according to claim 114 , wherein saidformulation further comprises bisantrene or amsacrine.
 122. Theapparatus according to claim 114 , wherein said formulation furthercomprises a taxane.
 123. The formulation according to claim 122 ,wherein said taxane is paclitaxel or doxytaxel.
 124. An inhalation maskfor administering aerosols to an patient comprising: a. means forenclosing the mouth and nose of said patient, having an open end and aclosed end, said open end adapted for placing over the mouth and nose ofsaid patient; b. upper and lower holes in said closed end adapted forinsertion of a nose outlet tube and a mouth inhalation tube; c. saidnose outlet tube attached to said upper hole, adapted to accept exhaledbreath from the nose of said patient; d. a one way valve in said nosetube adapted to allow exhalation but not inhalation; e. said mouthinhalation tube having an outer and an inner end, partially insertedthrough said lower hole, said inner end continuing to end at the rear ofsaid patients mouth, said inhalation tube end cut at an angle so thatthe lower portion extends further into said patients mouth than theupper portion and adapted to fit the curvature of the rear of saidpatients mouth; and f. a y-adapter attached to the outer end of saidmouth inhalation tube.
 125. The mask according to claim 124 , furthercomprising a moderate vesicant present in said inhalation tube.
 126. Themask according to claim 124 , further comprising a severe vesicantpresent in said inhalation tube.
 127. Any and all novel features orcombination of features, disclosed in the specification of thisapplication.